Conclusion: Through cellular uptake and cytotoxicity experiments we show the effective delivery and selective therapeutic effect of 211At-MABG in malignant mouse pheo cells as a proof of concept for future pre-clinical studies.
Acknowledgements and Support: Pheo-Para Alliance (DAP), Ultratrace Resin provided by Progenics. The project described was supported in part by Grant Number UL1RR024134 from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the offical views of the National Center for Research Resources or the National Institutes of Health. Supported in part by the Institute for Translational Medicine and Therapeutics’ (ITMAT) Transdisciplinary Program in Translational Medicine and Therapeutics. MPC cell lines were a kind gift from Drs. Powers and Tischler.
A Practical Method to Determine the Site of Unknown Primary in Metastatic Neuroendocrine Tumors
Jessica E. Maxwell, MD, MBA,1 Scott K. Sherman, MD,1 Kristen M. Stashek, MD,2 Thomas M. O’Dorisio, MD,3 Andrew M. Bellizzi, MD,4 James R. Howe, MD.11Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA; 2Department of Pathology, Hospital of the University of Pennsylvania, Philadelphia, PA; 3Department of Medicine, University of Iowa Carver College of Medicine, Iowa City, IA; 4Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA.
Background: The primary tumor site is unknown in approximately 20% of small bowel (SBNET) and pancreatic (PNET) neuroendocrine tumors despite optimal workup. Biopsies of PNET and SBNET metastases are histologically similar, yet knowing the primary site has important therapeutic and prognostic implications. We compared the utility of a three-marker immunohistochemistry (IHC) panel to our previously defined gene expression classifier (GEC) to determine the primary site of NET metastases.
Methods: RNA was extracted from 109 SBNET and PNET liver and lymph node metastases, and gene expression determined using qPCR. The GEC uses expression of BRS3 and OPRK1 in metastases to determine site of origin. The IHC algorithm uses CDX2, PAX6 and ISLET-1 to differentiate between tissues. It was evaluated in 86 primary SBNETs and PNETs and 37 metastases. NETs negative for all three markers were considered indeterminate. IHC was assessed by a pathologist blinded to the primary site, and results compared to those of the GEC.
Results: The GEC correctly identified the primary site in 76/78(97%) SBNET and 27/31(87%) PNET metastases. IHC correctly classified 83/86(97%) primary SBNETs and PNETs. In metastases, IHC called 33/37(89%) correctly, with 4 indeterminate. In the 27 metastases tested by both GEC and IHC, 26/27(96%) were correctly classified by GEC. IHC correctly classified 23/27(85%) samples, while the remaining 4 had “indeterminate” staining. All NETs missed by one method were correctly classified by the other.
Conclusion: Three-marker IHC is a simple and accurate initial test to determine the primary site from NET metastases. Although it made no incorrect classifications, 15% of metastases were indeterminate, necessitating a supplemental test. Our GEC demonstrates excellent overall accuracy (94%), and identified the primary tumor site in all cases where IHC failed. This suggests that performing IHC, followed by GEC for indeterminate cases, will identify the primary site of SBNET and PNET metastases in virtually all patients.
Exploration and Targeting of Neuroendocrine Cancer Tumorigenic Signal Transduction
Karine Pozo,1,2* Angela Carter,1,2* Florian Plattner,1,2 Gabriel Mettlach,1,2 Tanvir Singh,1,2 Hans Ghayee,2,3 Herb Chen,4 Fiemu Nwariaku,2,5 James A. Bibb.1,2,61Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX; 2Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical, Center, Dallas TX; 3Department of Endocrinology, The University of Texas Southwestern Medical Center, Dallas TX; 4Endocrine Surgery Research Laboratory, University of Wisconsin Carbone Cancer Center, Madison, WI; 5Department of Surgery, The University of Texas Southwestern Medical Center, Dallas TX; 6Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas TX. *Equal contributors.
Background: Neuroendocrine (NE) and neuronal cells both arise from neural tube ectodermal progenitors. They share common mechanisms of calcium-dependent exocytosis, neurotransmitter/hormone synthesis, and signal transduction. The protein kinase, Cdk5 mediates these overlapping functions. Excitotoxic dysregulation of Cdk5 is a critical contributor to neuronal injury and death during ischemia or brain injury. In contrast, in NE cells, Cdk5 dysregulation and invocation of pathways overlapping with those mediating brain injury results in neoplasia and tumorigenesis.
Methods: Here we employ a multidisciplinary approach including human tissue histopathology and immunohistology, advanced mouse modeling transgenics, in vivo imaging, electron microscopy, pharmacology, biochemistry, mass spectroscopy, cell biology, high through put screening, and phosphorylation state-specific antibody technology, and DNA array analysis to explore the mechanisms of NE cancer tumorigenesis.
Results: We demonstrated Cdk5 expression and aberrant activity in thyroid C cells and medullary thyroid carcinoma. Cdk5 inhibition arrested MTC cell growth. Transgenic induction of aberrant Cdk5 caused robust and lethal MTC in mice. We now find Cdk5 and p35 expression in many other NE tumor types and growth of neoplastic cells derived from a variety of NETs are Cdk5-dependent. We derived a tumorigenic signal transduction mechanism library consisting of protein phosphorylation sites up-regulated in growing versus arrested mouse MTC tumors. High-throughput screening of these mechanisms yielded anti-neoplasia SIPs with specific cytotoxicity toward neoplastic MTC cells, but not normal human cell controls.
Conclusion: We believe that different forms of NE cancer share common or overlapping tumorigenic mechanisms. We aim to develop a personalized diagnostic panel based on phosphorylation state-specific antibodies to these pathways and couple it to targeted therapies to more effectively treat NE cancer.
Autophagy Activation, a Survival Mechanism for pNETs Treated With mTOR Inhibitors
Hala E. Thomas,1 Carol A. Mercer,1 Sara C. Kozma,1,2 George Thomas,1,2 Lowell B. Anthony.31Department of Internal Medicine, University of Cincinnati, Cincinnati, OH; 2Catalonian Institute of Oncology/IDIBELL, Barcelona, Spain; 3Department of Internal Medicine, University of Kentucky, KY.
Background: The effects of the mTOR allosteric inhibitor RAD001 are more pronounced in pancreatic neuroendocrine tumors (pNETs) than in other tumor types; however resistance occurs, underscoring the need for novel lines of therapy. Based on our published studies in hepatocellular carcinoma, we propose to improve the clinical response to RAD001 in pNETs and in parallel counteract the development of RAD001 resistance by combining RAD001 with a dual PI3K/mTOR ATP-site-competitive inhibitor, which acts synergistically to completely inhibit mTOR.
Methods: Human BON cells (gift from C. Townsend at UTMB) were generated to stably express a doxycycline (Dox)-inducible shRNA targeting the autophagy gene ATG3 (shATG3) or a non-silencing control (shNS).
Results: The inhibitory synergy on proliferation we noted previously between RAD001 and BEZ235 is not unique to RAD001/BEZ235, as we can recapitulate this response in BON cells treated with RAD001 or rapamycin combined with the PI3K/mTOR ATP-site competitive inhibitor PKI-587 (gift from Pfizer). In BON cells the rapamycin/PKI-587 combination profoundly inhibited phosphorylation of key downstream mTOR targets including 4E-BP1, Akt and ULK1 and activated AMPK. To determine if the induction of autophagy by rapamycin/PKI-587 promotes or inhibits tumorigenesis in pNETs, we disrupted autophagy by depleting ATG3 in BON cells using an inducible shATG3-expression system. Impaired autophagy partially rescued the proliferation inhibition conferred by the combination treatment, compared to shNS control cells. Conversely, activation of autophagy using the disaccharide trehalose impaired BON cell proliferation.
Conclusions: These data support that the induction of autophagy in pNETs is anti-tumorigenic and that AMPK functions potentially as a tumor suppressor, not a resistance mechanism to mTOR/PI3K inhibitor treatment in these tumors. A deeper mechanistic understanding is warranted to determine if combining mTOR inhibitors with activators of autophagy or AMPK would be beneficial for the treatment of pNETs.
Molecular Profiling of Advanced Stage Neuro Endocrine Tumors (NETs): The Fox Chase Cancer Center (FCCC) Experience
Namrata Vijayvergia,1 Patrick M. Boland,1 Karen S. Gustafson,1 Fathima Sheriff,1 Harry Cooper,1 Steven J. Cohen,1 Igor Astaturov,1 Paul F. Engstrom.11Fox Chase Cancer Center, Philadelphia, PA.
Background: NETs are rare making clinical trial accrual challenging. Given fewer approved therapies, a better understanding of underlying biology can help development of and assignment of patients to clinical trials.
Methods: Patients with advanced stage NETs (excluding small/large cell lung cancer) of all grades at FCCC were enrolled onto a prospective IRB approved protocol that utilizes an NGS platform to detect somatic mutations in targeted regions of 50 cancer-related genes (Cancer CodeTM). Archived tissue from primary or metastatic site was analyzed for mutations in ABL1, AKT1, ALK, APC, ATM, BRAF, CDH1, CDKN2A, CSF1R, CTNNB1, EGFR, ERBB2,ERBB4, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, FLT3, GNA11, GNAQ, GNAS, HNF1A,HRAS, IDH1, IDH2, JAK2, JAK3, KDR, KIT, KRAS, MET, MLH1, MPL, NOTCH1,NPM1, NRAS, PDGFRA, PIK3CA, PTEN, PTPN11, RB1, RET, SMAD4, SMARCB1, SMO,SRC, STK11, TP53 and VHL genes. Central review of pathology specimens for grade/Ki −67% was done.
Results: Thirty-eight patients (median age 59 y, M: F ratio 0.9:1) were enrolled from October 2013 to May 2014. Ki-67 scoring was reviewed for 18/32 tumors. 4 (12%) patients had high grade tumors (Ki-67 > 20%) and 14 (43%) had low grade tumors (Ki-67 ≤20%). Gene profiling results are available on thirty-two patients. Twelve patients (38%) were found to have tumor specific mutations and twenty (62%) did not. 4 (12%) patients harbored >1 mutation [KRAS/RB1, BRAF/PIK3CA, TP53/KRAS (2)]. 30% (4/14) patients with low-grade NETs were mutation positive while all (4/4) of the high-grade NETs had tumor specific mutation(s) (BRAF/TP53/PIK3CA, BRAF, TP53, KRAS/TP53). Mutations according to the primary site are described in Table 1.
Conclusion: Tumor specific mutations are seen in a minority of low grade NETs but are common in high grade tumors. Many of these may guide future therapies and participation in clinical trials. Enrollment continues and collaborations between centers may help to identify trends in a larger population.
Incidence, Prevalence and Survival of Patients With Small Bowel Neuroendocrine Tumors (MGC) Excluding Appendiceal Tumors: A Northern Ireland (NI) Study Over 25 Years
Joy Ardill,1 Wendy Stronge,1 David McCance,1 Brian Johnston.11NET Group, Royal Victoria Hospital Belfast and Queen’s University, Belfast, Northern Ireland, UK.
Background: Incidence of MGC is 0.5-1/100,000/year and is said to be rising, perhaps due to improved diagnosis rather than a true incidence increase. Improving survival has been slow to confirm, even with the increase in treatment options in the last decade. ENETS and UKINETS emphasize the importance of patient management in NET specialist centers (NSC) with multidisciplinary team (MDT) input. We have had a NSC since 1978 with an MDT since 2000.
Methods: Data collection used the NI Cancer Registry, NET Clinic records, NI pathology records, Regulatory Peptide Laboratory records and patient clinical notes. MGC was diagnosed by pathology or by syndrome, radiology and biomarkers. Population in NI was obtained from census data. Data 1988–2012 was collected with survival follow up to 6/30/2014
Results: Between 1988 and 2012, 313 individuals with MGC were diagnosed, 335 were included for prevalence calculations. Diagnosis was secured by pathology in 94%. M/F ratio was 52/48. The incidence and prevalence of small bowel NETs over 25 years in NI is shown in Table 1. Since 1/1/2000, 199 patients with MGC and survival follow up were identified, 135 attending the NSC. Those surviving <3M were excluded. Comparing survival non-NSC to NSC patients, 1Y survival improved from 72.7% to 95.4.1%, 2Y 46.5% to 81.67% and 4Y 24.4% to 46.5%. On 6/30/2014 62.8% of NSC patients were alive compared to 18.2% of non-clinic patients. To remove age bias patients were age matched for age at diagnosis (+/−6m) NSC and non-clinic patients (60:60 patients). Survival was significantly better in the NSC patient group (Log Rank Test, P<0.019).
Conclusion: In this small insular population, incidence of MGC shows an increase 1988–2012. Survival is significantly improved when patients attend the NSC.
Poor Prognosis in Spontaneous Gastrinoma When Additional Hormones and Peptides Are Secreted
Joy Ardill,1 Brian Johnston,1 David McCance.11NET Group, Royal Victoria Hospital Belfast and Queen’s University Belfast, Northern Ireland, UK.
Background: Gastrinoma (ZES) occurs in 0.5–3/million/year. ZES may be familial (MEN1) or spontaneous, benign or malignant. Tumors in patients with MEN1 or those that are spontaneous may produce other peptides and hormones in addition to gastrin.
Methods: We studied patients with ZES who attended our clinic. Clinical notes and laboratory records were examined.
Results: Fifty seven patients had ZES, 13 with MEN1 and 44 with spontaneous tumors. Of the spontaneous group 7 were benign and 37 malignant. Thirteen of those with malignant tumors later secreted additional hormones.
MEN1 patients presented with circulating gastrin 900 (125–3,200) ng/l, eight had tumours secreting other peptides and hormones including PTH, prolactin, insulin, glucagon, PP, somatostatin, VIP, calcitonin or NKA. Several patients had multi-hormone secretion. Median survival was 17 (3–34) years.
Patients with benign tumors presented with circulating gastrin 260 (130–1,050) ng/l all were cured by surgery. Survival in each individual was >17years.
Twenty four patients with metastatic ZES presented with circulating gastrin 500 (145–15,800) ng/l, and median survival was 8.2 (0.5–26) years. None of these patients secreted additional peptides with the exception of PP <2,500ng/l. (PP is secreted by many pancreatic NETs. PP secreted by PPoma is usually >10,000ng/l)
Thirteen patients with metastatic ZES presented with gastrin 750 (255–70,000) ng/l. All in this group later secreted additional hormones, PTH, prolactin, PP, insulin, glucagon, VIP, NKA, somatostatin or calcitonin. Several patients secreted 2 or 3 additional hormones. Median survival was 1.9 (0.1–9.9) years. No patient survived more than 2 years post multi-hormone secretion. Those producing ACTH, PP (>20,000ng/l) or insulin had poor survival.
Conclusions: A third of patients with spontaneous metastatic ZES later secrete additional hormones resulting in worse prognosis. ZES patients should therefore be screened regularly, using relevant biomarkers, making possible, earliest appropriate treatment intervention.
Health-Related Quality of Life (HRQL) in Patients With Uncontrolled Neuroendocrine Tumor (NET) Symptoms
Jennifer L. Beaumont, MS,1 Maureen Neary, PhD,2 Zhimei Liu, PhD,2 James C. Yao, MD,3 David Cella, PhD.11Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago IL; 2Novartis Pharmaceuticals Corporation, East Hanover, NJ; 3Gastrointestinal Medical Oncology, University of Texas M D Anderson Cancer Center, Houston TX.
Background: The HRQL of patients with NET may be impacted by treatment and severity of symptoms. The objective of this project was to explore the HRQL impact of uncontrolled symptoms, namely diarrhea, in a cross-sectional survey.
Methods: Patients with NET were invited via email to participate in an online anonymous survey consisting of demographics, disease-related questions and standardized measures of HRQL (SF-36 and PROMIS-29). We compared HRQL scores between groups of patients defined by whether or not they were currently receiving any treatment (yes vs no) and stratified by symptom severity (0–3 vs 4 or more bowel movements per day).
Results: Of the 663 patients who participated in the survey, 637 provided complete responses to questions about treatment and symptoms and 149 (23%) had not received treatment of any kind in the past month. Patients with 0–3 bowel movements per day reported HRQL scores similar to the general population mean of 50, regardless of whether or not they were receiving treatment. Patients with 4 or more bowel movements per day reported HRQL scores worse than the general population, although those who were not treated reported better physical functioning scores than treated patients (see Table 1).
Conclusions: In this cross-sectional study, HRQL was negatively impacted by diarrhea, although physical functioning was somewhat better in treated patients. Longitudinal reports of HRQL are needed to evaluate the HRQL impact of symptom improvement.
Long Term Effects of Surgical Resection of Pheochromocytoma or Paraganglioma on Body Weights: A Retrospective Cohort Study
Bonita Bennett, RN,1 Anirban Ganguli, MD,1 Heather Wachtel, MD,2 Douglas Fraker, MD,2 Debbie L. Cohen, MD.11Division of Nephrology, Hospital of the University of Pennsylvania, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; 2Department of Surgery, Hospital of the University of Pennsylvania, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
Background: Removal of catecholamine secreting tumors have beneficial effects on BP control but long term effects on body weight and anthropometric measurements are not known. The study objective was to assess the trajectory of body weights in patients with pheochromocytoma (PCC) and paraganglioma (PGL) before and after surgical resection.
Methods: We conducted a retrospective chart review of all patients with new diagnosis of PCC/PGL from 2001 to 2011 who underwent surgical resection at Penn and had at least 2 years of follow up. Body weights were reviewed immediately prior to surgery, and at four time points (4–6 weeks, and 6, 12, and 24 months) postoperatively.
Results: Follow up data from 37 patients was available. Mean age of patients was 49.1 years with 62% females. Sporadic PCC/PGL was seen in 27 (72.0 %), MEN 2A in 1 (2.7%), neurofibromatosis in 1 (2.7%), vHL in 1 (2.7%), SDHD mutations in 3 (8.1%), SDHB mutations in 3 (8.1%). Laparoscopic tumor resection was performed in 48%. Hypertension was cured in only 36% while it persisted in 64%. Mean weight preoperatively was 84.1 ±19.9 kg; postoperative weight trend was 82.5 ± 19.2 kg, 83.2 ± 18.1 kg, 86.9 ± 20.5 kg and 88.0 ± 21.0 kg at 4–6 weeks, 6, 12, and 24 months, respectively. The mean 2 year weight gain was 3.9 ± 5.8 kg which was statistically significant (p=0.002).
Conclusions: Significant and sustained weight gain consistently occurred after successful removal of PCC/PGL. This underscores the long term role of catecholamines on resting energy expenditure. Chronic persistence of hypertension may be due to normalization of catecholamines with decreased metabolic rate and resultant weight gain. Clinical relevance includes use of body weight as a surrogate marker of successful tumor resection. Weight loss and hypertension exacerbation may be potential clinical markers of tumor recurrence.
Theranostics With I-131/I-123 Meta-Iodobenzylguanidine (MIBG) in Stage IV Advanced Malignant Neuroendocrine Tumors
Richard J Campeau,1 Eugene A Woltering,1 J Phillip Boudreaux,1 Yi-Zarn Wang,1 Robert A Ramirez.11FACNM LSU and Ochsner Health Sciences Centers, Ochsner Medical Center-Kenner, Neuroendocrine Tumor Clinic, Kenner, LA.
Background: Clinical outcomes of a group (n=50) of unselected Stage IV NETs (all types and grades), scanned and treated with I-123/I-131 MIBG were evaluated at a single center multidisciplinary specialty clinic. These unselected advanced NETs were compared with all grades of small bowel (SB) NETs as well as G1 SB NETs for outcomes.
Methods: This study began in June of 2008, and continued to June of 2014. NET patients, receiving standard of care (SOC) consisting of cytoreductive surgery, and multidisciplinary care were selected from our active NET Clinic. Subjects had to demonstrate progressive disease while receiving SOC, and demonstrate intense uptake of the I-123 MIBG radiopharmaceutical in all tumor sites larger than 1.0 cm. Clinical outcomes and Kaplan-Meier survival rates from histological diagnosis were recorded.
Results: In an unselected population of NETs, many with aggressive histology, 46% of patients improved symptoms after I-131MIBG treatment. 54% were stable, or worsened symptomatically (34% and 20%, respectively). Only a minority (10%) showed any radiographic response, and there were no CRs. After 6.0 yrs of follow up from MIBG treatment, 44% of these patients were still alive. In SB (all grades) carcinoids, early survival was similar to all types of NETs, but after 10 yrs from diagnosis, SB carcinoids (G1, G2, G3), treated with I-131 MIBG had significantly better survival (at least 20% better) than the population of all NETs. When MIBG treated non-well differentiated SB carcinoids were excluded, there was further improvement in survival from histological diagnosis. G1 SB carcinoids treated with I-131 MIBG had an additional further survival advantage of 21% (41% greater than unselected NETs).
Conclusions: I-131MIBG is most valuable in treatment of well differentiated carcinoid tumors with survival advantage of at least 40% over unselected NETs and a 20% survival advantage over intermediate and high grade carcinoid tumor patients.
Antitumor Effects With Lanreotide Autogel/Depot (LAN) in Patients With Metastatic Enteropancreatic (EP) Neuroendocrine Tumors (NETs): Interim Results of the CLARINET Extension Study
Martyn E. Caplin,1 Alexandria T. Phan,2 Philippe Ruszniewski,3 Marianne E. Pavel,4 Jarosław B. Ćwikła,5 Markus Raderer,6 Eva Sedláčková,7 Guillaume Cadiot,8 Lucy Wall,9 Guido Rindi,10 Alison Langley,11 Edda Gomez-Panzani,12 on behalf of the CLARINET study group. 1Royal Free Hospital, London, UK; 2Houston Methodist Hospital Cancer Center, TX; 3Beaujon Hospital, Clichy, France; 4Charité University Medicine Berlin, Berlin, Germany; 5University of Varmia and Masuria, The Faculty of Medical Sciences, Olsztyn, Poland; 6University Hospital, Vienna, Austria; 7First Faculty of Medicine and General Teaching Hospital, Prague, Czech Republic; 8Robert-Debré Hospital, Reims, France; 9Western General Hospital, Edinburgh, UK; 10Università Cattolica del Sacro Cuore, Rome, Italy; 11Ipsen, Les Ulis, France; 12Ipsen Biopharmaceuticals, Inc., Basking Ridge, NJ.
Background: The CLARINET core study showed that the long-acting somatostatin analog LAN significantly prolonged progression-free survival (PFS) vs. placebo in patients with metastatic grade 1 or 2 (Ki-67 <10%) EP-NETs (p<0.001); median LAN PFS not reached during the 24-month study (vs. 18.0 months with placebo). We report safety and PFS data from the planned interim analysis of the single-arm (LAN) open-label extension (OLE; NCT00842348).
Methods: Patients entering CLARINET had: metastatic well/moderately differentiated non-functioning EP-NETs with Ki-67 <10%; no prior somatostatin analog or other medical therapy use in last 6 months; documented disease-progression status. Patients were randomized to LAN 120 mg (n=101) or placebo (n=103) every 28 days for 96 weeks or until death/progressive disease (PD; according to RECIST 1.0). Patients at continuing study centers could enter the OLE if they had: stable disease (SD) at core-study end or PD on core-study placebo. Primary OLE objective was safety; secondary OLE objective was to investigate further LAN efficacy.
Results: Eighty-eight CLARINET patients (LAN arm, n=41; placebo arm, n=47) had entered the OLE at interim analysis. At core-study enrollment, 96% of OLE patients had SD; 38% had pancreatic and 39% midgut primary tumors. Median LAN PFS (time from randomization in CLARINET to death/PD in either study) was reached in the OLE: 32.8 months. For patients with PD on CLARINET placebo, median time to further PD after switching to LAN in the OLE was 14.0 months. During the OLE, 27% who continued LAN vs. 40% who switched to LAN had treatment-related adverse events (TRAE). The most frequent TRAE was diarrhea. No new safety concerns were identified.
Conclusions: CLARINET OLE data suggest longer-term LAN treatment is well tolerated. The results also help indicate the longer-term benefits of LAN in EP-NET patients with SD, and suggest LAN has antitumor effects in EP-NET patients with PD.
Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) and the Role of Somatostatin Analogs
Aman Chauhan,1 Robert A. Ramirez.21PGY IV Resident Internal Medicine and Pediatrics; LSUHSC New Orleans, New Orleans, LA; 2Department of Hematology and Oncology, LSUHSC New Orleans, New Orleans, LA.
Background: DIPNECH is a rare pre-neoplastic condition that often presents with a variety of non-specific pulmonary symptoms and sometimes seen in conjunction with pulmonary carcinoid tumors. There is no published data on use of somatostatin analogs in patients with DIPNECH. We review the long term outcomes of somatostatin analog therapy with regard to symptom control in patients with DIPNECH.
Methods: Retrospective study out of our registry of over 2000 neuroendocrine tumors identifying 184 pulmonary neuroendocrine tumors. Out of this there were 5 histopathologically confirmed cases of DIPNECH. Appropriate institutional review board permission was taken for this analysis.
Results: All 5 patients were females, with a mean age at diagnosis of 65.5 years. Median follow up period was 9 years. Cough was the presenting complaint in all 5 patients described as mostly dry, except for one patient who had productive early morning cough. Other symptoms seen in one patient included wheezing, flushing and fluctuating blood pressure. No one reported weight loss, hemoptysis and shortness of breath. One of our patients had a benign thyroid nodule and two patients had previous history of breast cancer. All five of our patients were histopathologically diagnosed with an open lung biopsy. 4 out of 5 patients were started on somatostatin analog. All four patients reported significant improvement in cough. One patient reported mild abdominal discomfort and diarrhea as side effects but remained on treatment. Chromogranin A levels were followed and declined in all but one patient following initiation of somatostatin analog.
Conclusions: From our single institution review of pulmonary neuroendocrine tumors we found only 5 cases of DIPNECH, which reaffirms the rare nature of this pathology. It primarily affects females over 60 years with dry cough as the most common presenting symptom. Most of our patients responded to treatment with a somatostatin analog and had significant improvement in their presenting symptoms. Trending chromogranin A levels seemed to correlate with clinical improvement while the patients were on a somatostatin analog. Somatostatin analogs were well tolerated. Further research is needed in this rare condition, however, a trial of somatostatin analogs should be considered in the treatment of patients with DIPNECH with responders being treated long term.
Chemotherapy for Locally Advanced and Metastatic Pulmonary Carcinoid Tumors
Curtis R. Chong,1 Lori J. Wirth,2 Mizuki Nishino,1 Aileen B. Chen,1 Lynette M. Sholl,1 Ciaran J. McNamee,1 Pasi A. Jänne,1 Bruce E. Johnson.11Dana-Farber Cancer Institute, Boston, MA; 2Massachusetts General Hospital Cancer Center, Boston, MA.
Background: The optimal management of locally advanced and metastatic pulmonary carcinoid tumors remains to be determined.
Materials and methods: A retrospective review was conducted on patients with typical and atypical pulmonary carcinoid tumors treated at our institutions between 1990–2012.
Results: 300 patients were identified with pulmonary carcinoid, (80 patients with atypical carcinoid), of whom 29 presented with metastatic disease (16 atypical). Of evaluable patients, 26 (41%) with stage I-III atypical carcinoid tumors recurred at a median time of 3.7 years (range, 0.4–32), compared to 3 (1%) patients with typical carcinoid (range, 8–12.3). 39 patients were treated with chemotherapy, including 30 patients with metastatic disease (27 atypical), and 7 patients were treated with adjuvant platinum-etoposide chemoradiation (6 atypical, 1 typical, 6 stage IIIA, 1 stage IIB). At a median follow-up of 2 years there were 2 recurrences in the 7 patients receiving adjuvant treatment. Median survival after diagnosis of metastatic disease for patients with atypical pulmonary carcinoid was 3.3 years with a 5 year survival of 24%. Treatment regimens showing efficacy in pulmonary carcinoid include 15 patients treated with octreotide-based therapies (10% response rate (RR), 70% disease control rate (DCR), 15 month median progression-free survival (PFS)), 13 patients treated with etoposide + platinum (23% RR, 69% DCR, 7 m median PFS), and 14 patients treated with temozolomide-based therapies (14% RR, 57% DCR, 10 m median PFS). 8 of 10 patients with octreotide-avid disease treated with an octreotide-based regimen experienced disease control (1 partial response, 7 stable disease) for a median of 18 months (range 6–72 months).
Conclusions: These results support our previous finding that a subset of pulmonary carcinoid tumors are responsive to chemotherapy.
A Phase II Study of Axitinib in Advanced Carcinoid Tumors
Mauro Cives,1 Jonathan Strosberg,1 Tiffany Campos,1 Thomas Weber,2 McKinley Nickerson,2 Tiffany Valone,1 Domenico Coppola,1 Emily Bergsland.21H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; 2The Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.
Background: Neuroendocrine tumors (NETs) are highly vascularized neoplasms overexpressing VEGF as well as VEGFR. Axitinib is an inhibitor of receptor tyrosine kinase with selective picomolar potency against VEGFR-1, −2 and −3 and nanomolar potency against PDGFR-β.
Methods: We performed a phase II trial of axitinib 5 mg BID in patients with unresectable or metastatic low to intermediate grade carcinoid tumors. Prior antiangiogenic therapy with a dedicated VEGF pathway inhibitor was not permitted. The primary endpoints were PFS and 1-year PFS rate. H0=12 mo PFS rate of 36% (corresponding to median PFS of 8.1 months); Ha= 12 mo PFS rate of 56.5% (corresponding to median PFS of 14.6 months). Preliminary findings are reported.
Results: 30 patients were enrolled and assessable for toxicity; 22 were assessable for response. Primary sites included small intestine (19 patients), lung (3), unknown (3), colon (2), rectum (2), and thymus (1). 21 patients had low-grade and 9 patients had intermediate-grade tumors. Median TTF was - 8.99 months (SD ±7.18 ) and the 12-month PFS rate was 65% (SD ±13%). The 1-year OS rate was 93% (SD±4.9%). Median PFS not yet determined due to small number of events. Best radiographic response was PR in 1/30 (3.3%) and stable disease in 21/30 (70%); 8/30 patients (27%) unevaluable. Among 25 patients with baseline elevated CgA levels, only 4 experienced major reductions (>50%) of the tumor marker. Axitinib treatment was associated with a 90% rate of hypertension. Grade 3 and 4 hypertension were seen in 18 (60%) and 2 (7%) patients respectively and led to treatment discontinuation in two cases. However, axitinib interruption prompted a fast recovery without sequelae.
Conclusions: The 12 mo PFS rate associated with axitinib in advanced carcinoid tumors is promising when compared to results observed in phase II studies of other antiangiogenic TKIs such as sunitinib or pazopanib. Although rates of hypertension were high, axitinib treatment was overall well tolerated.
Use of Molecular Profiling to Guide Treatment Decisions in Patients With Neuroendocrine Tumors
Holt S. Cutler,1 Paul Ogando,2 Joshua H. Uhr,1 Dani O. Gonzalez,2 Richard R.P. Warner,3 Celia M. Divino.41Icahn School of Medicine at Mount Sinai, New York, NY; 2Division of General Surgery, Mount Sinai Hospital, New York, NY; 3Director of the Center for Carcinoid and Neuroendocrine Tumors, Mount Sinai Hospital, New York, NY; 4Chief of the Division of General Surgery, Mount Sinai Hospital, New York, NY.
Background: Neuroendocrine tumors (NETs) constitute a rare orphan disease. As their incidence continues to increase, so does the need for effective treatments. Various cytotoxic and targeted therapies have had low response rates in trials, with a few exceptions. Predictive markers for specific therapies measured by molecular profiling of resected tumor tissue could potentially improve selection of treatments and lead to better responses.
Methods: Resected carcinoid tumor samples at one institution were sent for molecular profiling over a 3-year period. Molecular profiling tests were ordered to measure the expression of twenty proteins and oncogenes using immunohistochemical staining, gene sequencing, and fluorescent in-situ hybridization. Potentially beneficial systemic therapies were identified by comparing these biomarker levels against a comprehensive review of the chemotherapy response literature. The clinical charts of 41 patients who underwent molecular profiling and treatment from 2010 to 2012 were reviewed retrospectively, and 12 were selected for our case series to represent the range of effects molecular profiling has had on carcinoid treatment. Their presentation, molecular profile results, treatment, and disease progression is reviewed in the following case series.
Results: A total of 9 patients in this series were treated with drugs identified as potentially beneficial by molecular profile reports (see Table 1). These drugs include capecitabine, 5-fluorouracil, temozolomide, oxaliplatin, and gemcitabine. Based on clinical symptoms, serum markers of disease, and radiographic evidence 5 of 9 patients responded to treatment, 2 had mixed responses, and 2 did not respond to treatment. Grade 3 NETs do not appear to be well suited for treatment guided by molecular profiling at this time.
Conclusion: At this early juncture, our critique of molecular profiling for neuroendocrine tumors is favorable, as a significant number of our patients responded to drugs identified by molecular profiling as potentially beneficial.
The Prognostic Significance of Lymph Node Ratio in Carcinoid Tumors
Virginia Flatow,1 Richard Warner,2 Jessica Overbey,3 Celia M. Divino.41Department of Medical Education, Icahn School of Medicine at Mount Sinai Hospital, New York, NY; 2Department of Gastroenterology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY; 3Department of Health Evidence and Policy, Icahn School of Medicine at Mount Sinai Hospital, New York, NY; 4Department of Surgery, Icahn School of Medicine at Mount Sinai Hospital, New York, NY.
Background: Neuroendocrine tumors are an increasingly prevalent tumor occurring in roughly 5 per 100,000 persons. Carcinoid tumors, a subset of NET, are slow growing and frequently occur in the gastrointestinal tract. Several studies have highlighted the prognostic significance of nodal metastases in carcinoid tumors. Currently, The American Joint Committee on Cancer (AJCC) only uses the presence (N1) or absence (N0) of regional node metastases as a prognostic indicator in carcinoid tumors., however some research suggests that lymph node ratio may be a superior way to evaluate nodal involvement in cancer. 1–5 However, no research to our knowledge has evaluated lymph node ratio in carcinoid tumors. The aim of this study was to evaluate whether lymph node ratio (LNR) is a better predictor of survival than N1 of 10-year survival in carcinoid tumors.
Methods: 11,189 individuals with carcinoid tumors who were recorded in the Surveillance, Epidemiology, and End Results (SEER) database between 1988–2010 were evaluated. Carcinoid tumors were classified according to ICD-O-3 histology codes. The Kaplan-Meier estimator was used to evaluate overall survival. Receiver operator curves (ROC) and the area under the ROC curve (AUC) were used to evaluate the ability of nodal involvement or lymph node ratio to predict ten-year survival. All analyses were performed using STATA and SAS v9.3.
Results: ROC curve analysis indicated that LNR and node positivity were both predictive of ten-year survival, AUC .734, p < .0001, AUC 0.7048, p < .0001. LNR was 88% specific and 50% sensitive in predicting ten-year survival. N1 was 88% specific and 49% sensitive in predicting ten-year survival. Both LNR and N1 were the most (100%) specific in predicting 10-year survival for patients with carcinoid tumors located outside of the fore, mid, or hindgut region with a 61% (N1) and 70% (LNR) sensitivity. LNR and N1 were most (86%) sensitive in predicting ten-year survival in patients with carcinoid tumors of the foregut with a 53% (N1 and LNR) specificity.
Conclusion: We believe that LNR is an important independent predictor of survival for individuals with carcinoid tumors. However, LNR only provides a modest benefit when compared with the binary predictor of whether or not there are positive regional nodes.
Response to Capecitabine and Temozolomide in an Adolescent Female With Metastatic, Non-functional Pancreatic Neuroendocrine Tumor
Leslie Gilbert, MD,1 Adam Bobbey, MD,2 Kristen Snyder, MD.11Division of Pediatric Hematology Oncology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN; 2Department of Radiology, Vanderbilt University Medical Center, Nashville, TN.
Background: Pancreatic neuroendocrine tumors are rare with an estimated overall incidence of <1/100,000. Aggressive surgical resection is advocated as first line therapy. However, approximately half of tumors are metastatic at presentation limiting the ability for complete resection.
A 13-year-old African American female presented with two years of intermittent, dull, epigastric pain. CT scan revealed a 2 cm mass in the pancreatic tail and multiple hepatic lesions. Imaging with PET scan, bone scan, and spine MRI revealed involvement of multiple thoracic and lumbar vertebrae. Liver lesion biopsy was consistent with metastatic pancreatic neuroendocrine tumor (mPNET). Octreoscan revealed no uptake within the pancreatic mass. The family initially declined chemotherapy due to concerns of quality of life. Her pain subsequently worsened requiring narcotics. Fourteen months after diagnosis, she suffered a pathologic fracture of her right femoral neck requiring hemiarthroplasty. Given symptomatology and progressive disease, they agreed to a chemotherapeutic regimen, 15 months after diagnosis, with capecitabine 750 mg/m2/dose twice daily for 14 days and temozolomide 250 mg/m2/dose daily on days 10–14. She had no adverse events attributed to therapy. CT scan after two cycles showed decreased size of a left breast lesion (2.3 cm to 2 cm), a right anterior mediastinal mass (4.2 x 3.4 cm to 2.5 cm x 1.7 cm), and a left hepatic lobe lesion (14.6 cm to 12 cm). Representative images are shown in Figure 1. The patient received two additional cycles of therapy prior to further disease progression and death 20 months after diagnosis.
Conclusions: This case highlights the hesitance of patients to receive chemotherapy for a rare, and slow growing, but fatal disease when little literature exists in the pediatric population. In addition, it demonstrates the feasibility, disease response, and minimal toxicities associated with this regimen in a pediatric patient with extensive mPNET treated late in the disease process.
Small Intestine Neuroendocrine Tumors: Frequently of Unrecognized Primary Site and Multifocal
Zafir Javeed,1 Yucheng Wang,1 David B. Donner,1 Emily K. Bergsland,1 Robert S. Warren,1 Eric K. Nakakura.11UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA.
Background: Because small intestine neuroendocrine tumors (SI-NETs) are typically small, arise from the submucosa, and grow outwardly into the mesentery, they are frequently not identified despite extensive preoperative evaluation in patients with biopsy-proven neuroendocrine liver or lymph node metastases. In such cases, the primary site is considered unknown. However, evidence is accumulating that most NETs of unknown primary can be found by surgical exploration. Moreover, there is conflicting data on the incidence of multifocal primary tumors, which should be identified and removed at the time of surgery.
Methods: We conducted a retrospective cohort analysis of patients who underwent resection of SI-NETs from 2005 to 2014 at an academic medical center where surgical exploration and careful palpation of the small intestine is done to identify unknown primary tumors and multifocal primaries.
Results: Fifty-nine patients underwent resection of SI-NETs. Preoperatively, nearly two-thirds of patients (37/59; 62.7%) had an unknown primary tumor, and all primary tumors were found by surgical exploration (34 in the ileum, 3 in the duodenum). Almost half of patients (26/59; 44.1%) had multifocal tumors. Patients with multifocal tumors were older (mean age = 65 yo vs. 57 yo). The size of the largest tumor in patients with multifocal tumors (mean = 2.2 cm; median = 2 cm) did not differ from that of unifocal tumors (mean = 2.2 cm; median = 2 cm). Most patients had lymph node metastases; however, no lymph node metastases were detected in one patient (3.8%) with multifocal tumors and two patients (6.1%) with unifocal tumors.
Conclusion: At an academic medical center, most patients who underwent surgery for SI-NETs had an unknown primary tumor. Surgical exploration successfully identified all primary tumors in this series despite a negative preoperative workup. The ileum is the most common site from which SI-NETs arise. When careful palpation of the small intestine is routinely done, multifocal primary tumors were identified in nearly half of patients who underwent SI-NET resection. For patients with a NET of unknown primary, the primary site is really not unknown; rather, it is unrecognized. For carefully selected patients, surgical exploration will effectively identify the primary site, which is typically in the ileum. The small intestine should be palpated routinely to identify multifocal primary tumors, so they can be resected.
Elevated Serum Pancreastatin is an Indicator of Hepatic Metastasis in Patients With Small Bowel Neuroendocrine Tumors
Tahsin M. Khan,1 Malika Garg,1 Richard R.P. Warner,2 Joshua H. Uhr,1 Celia M. Divino.1* 1Division of General Surgery, Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY; 2Division of Gastroenterology, Department of Medicine, Center for Carcinoid and Neuroendocrine Tumors, Icahn School of Medicine at Mount Sinai, New York, NY. *Corresponding Author.
Background: Serum pancreastatin has greater sensitivity and specificity in diagnosing neuroendocrine tumors (NETs) than serum chromogranin A (1). Additionally, elevated pancreastatin levels are associated with worse progression free survival and overall survival in small bowel and pancreatic NETs (2). In this study, we investigated the clinical significance of elevated serum pancreastatin in identifying metastatic disease to the liver.
Methods: A retrospective chart review of patients with NET managed at a single institution was performed. The site of primary NET, laboratory data, and presence of metastatic disease was reviewed. Sensitivity, specificity, positive predictive value, and negative predictive value for pancreastatin and chromogranin A as indicators of liver metastasis were ascertained. Serum pancreastatin measurements were performed by Cambridge Medical, Boston, MA, using a quantitative radioimmunoassay.
Results: Data was abstracted from 77 patients (54% female, n= 42). Small bowel was the primary tumor site in 44 patients (57%). Metastatic disease to the liver was noted in 49 patients (64%). Elevated serum pancreastatin was found to be more sensitive (85.7% vs. 61.5%) and specific (66.7% vs. 43.8%) than elevated chromogranin A in identifying liver metastasis in patients with primary tumors of the small bowel (see Table 1).
Conclusion: Elevated serum pancreastatin is a more sensitive and specific assay for detecting the incidence of liver metastasis in patients with small bowel NET compared to chromogranin A, which is the current preferred prognostic biomarker in NET. This study supports the usefulness for routine measurements of pancreastatin in patients with NET, especially in patients with disease arising from their small bowel.
A Multi-Gene Transcript Blood Molecular Signature for Gut Neuroendocrine Tumors (NETs) Delineates Surgical Efficacy
Mark Kidd,1 Daniele Alaimo,1 Stephen Callahan,1 Christopher Lepensky,1 Omar Faiz,2 Harpreet Wasan,2 Lei Weng,2 Panagiotis Drymousis,2 Nancy Smith Teixeira,1 Ignat Drozdov,1 Lisa Bodei,1 Andrea Frilling,1 Irvin M Modlin.11Wren Laboratories, Branford, CT; 2Imperial College London, London, UK.
Background: Biomarker prediction of therapeutic efficacy is a key clinical index. A blood multi gene signature for gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is a sensitive and specific biomarker for the detection of such neoplasia. Determination of tumor alteration in size is a key determinant of disease progress or regression. We propose that the extent of surgical cytoreduction should therefore be identifiable as a measure of therapeutic efficacy by blood gene transcript measurement and identify residual disease.
Methods: GEP-NETs (n=27) [M:F 14:13; age: 53 years, range: 37–74; stomach n=1, pancreas n=8, small intestine: n=14, appendix n=3, rectum n=1; G1=17, G2=10) were evaluated. There were (n=10) complete “R0” resections with 17 incomplete “R1/2” resections. Preoperative blood values and 1 month post-surgery were measured for 51 NET gene transcripts (GT) and CgA. A multianalyte algorhythmic analysis (MAAA) of RTPCR was used for the GT measurement and ELISA for CgA. Analyses included non-parametric paired testing and comparisons of MAAA and CgA as well as between R0 and R1/2.
Results: Surgical resection significantly reduced PCR scores (6.7±0.23 vs. 3.7± 0.3, p<0.0001); no significant decrease was identified for CgA (58.5±32.5 vs. 55.2±36.5, p=0.07). R0 versus R1/2 comparison revealed that post-surgical PCR scores were significantly lower (2.8±0.4 vs. 4.1±0.4, p<0.05) following R0 resection. The R0 group was also associated with greater decreases in this score (−58±6.5% vs. -40±6.5, p<0.05). Although post-operative imaging identified disease in n=1 (10%) elevated gene scores were evident in 6 (60%) at 1 month. Two R0 individuals developed positive imaging at 6 months.
Conclusion: Surgical cytoreduction can be demonstrated by diminution of the peripheral blood NET gene transcripts. Values correspond with extent of resection. GT analysis identified residual disease in 60% of R0 resections. CgA measurement was unable to define the effect of surgery or identify residual disease. Application of a PCR-based blood test will facilitate assessment of completeness of surgical resection and early identification of residual/recurrent disease thereby increasing the therapeutic window of opportunity for other agents.
Prognostic Significance of the Extent of Lymph Node Metastases in Small Intestinal Neuroendocrine Tumors
Michelle Kang Kim,1 Richard RP Warner,1 Stephen C. Ward,2 Noam Harpaz,2 Sasan Roayaie,3 Myron Schwartz,4 Steven Itzkowitz,1 Juan Wisnivesky.51Division of Gastroenterology, Department of Medicine, Mount Sinai School of Medicine, New York, NY; 2Department of Pathology, Mount Sinai School of Medicine, New York, NY; 3Liver Cancer Program, Hofstra-North Shore Long Island Jewish School of Medicine; 4Mount Sinai Liver Cancer Program; 5Division of Internal Medicine, Department of Medicine, Mount Sinai; School of Medicine, New York, NY.
Background: Current staging guidelines for small intestinal neuroendocrine tumors (SI-NETs) only differentiate between the presence (N1) and absence (N0) of lymph node (LN) metastases. However, the prognostic significance of the extent of LN involvement remains unknown. In this study, we used data from a national population-based cancer registry to examine whether involvement of a higher number of LNs is associated with worse survival.
Methods: We used the Surveillance, Epidemiology and End Results (SEER) database to identify patients with histologically confirmed, surgically resected SI-NETS diagnosed between 1988 and 2010. Patients were classified into three groups by the lymph node ratio (number of positive lymph nodes/number of total lymph nodes examined, LNR): ≤0.20, >0.20–0.5, and >0.5. We used the Kaplan Meier method to assess NET cancer-specific survival differences (up to 10 years from diagnosis) according to LNR status. We constructed Cox models to evaluate differences in prognosis after controlling for potential confounders.
Results: We identified 2,984 surgically resected patients with N1, non-metastatic SI-NETs with detailed LN data. More than half of NETs were located in the ileum. Higher LNR was significantly associated with worse NET cancer-specific survival (Figure 1, p<0.0001). Ten-year NET-specific survival was 85%, 77%, and 74% for patients in the ≤0.2, >0.2–0.5, and >0.5 LNR groups, respectively. In stratified analyses, higher LNR groups experienced worse survival only in early tumor (T1, T2) disease (p<0.0001). There were no differences in survival across LNR groups in patients with late tumor (T3, T4) status (T3, p=0.24; T4, p=0.40). Cox analysis confirmed a differential effect of LNR on NET-specific survival according to tumor category.
Conclusions: Extent of LN involvement provides independent prognostic information in patients with LN positive SI-NETs. This information may be used to identify patients at high risk of recurrence and inform decisions about use of adjuvant therapy.
Comparison of the Effectiveness of 68Ga-DOTATATE PET/CT and 111In-Octreotide SPECT in Patients With Somatostatin Positive Neuroendocrine Tumor
Meena Kumar,1 Shelly Broline,1 Reza Amerinia,1 Sanjay I. Thamake,2 David Ranganathan,2 Izabela Tworowska,2 Ebrahim S. Delpassand.11Excel Diagnostics & Nuclear Oncology Center, Houston, TX; 2Radiomedix, Inc., Houston, TX.
Background: Somatostatin analogues target five different somatostatin receptors (SSR) expressed on neuroendocrine tumors (NET). Octreoscan is currently the standard of care and only FDA approved and commercially available diagnostic test for well-differentiated NET. 111In-Octreotide has a high affinity for SSR2, and Octreoscan has lower image resolution than PET resulting in high detection failure of 20-50% of NET. In comparison, 68Ga-DOTATATE has a higher affinity for SSR2, and PET/CT has 2–3 fold higher spatial resolution than gamma camera imaging. The purpose of the study is to compare the effectiveness of 68Ga-DOTATATE PET/CT (Ga) to 111In-Octreotide SPECT (Octreoscan) in NET patients.
Methods: Seventy-nine patients underwent one Octreoscan on the ECAM Siemens dual detector gamma camera or equivalent camera and one Ga on the Biograph 16 Siemens PET/CT scanner. The Ga was performed ≤ 42 days of the Octreoscan (mean 4.1 days). Areas of abnormal uptake were compared with CT, MRI, bone scan, NaF and FDG PET/CT to confirm presence of lesions. The Octreoscan was read by a Nuclear Medicine physician (NM) blinded to the Ga results, and the Ga scan read by another NM blinded to the Octreoscan results. A consensus read was then performed. Lesions quantified were in organs, lymph nodes, and bones.
Results: Paired t-test analysis was performed. Ga shows significantly higher detection rate versus Octreoscan for organs (p-value of <0.0001), lymph nodes (p-value of <0.0001), bones (p-value of <0.0001), and combined organ, lymph node, and bone lesions (p-value of <0.0001) (see Table 1).
Conclusions: Ga PET/CT is more accurate for staging and superior to Octreoscan SPECT in the detection of overall number of lesions in the body as well as organs, lymph nodes, and bones. Ga PET/CT also allows for calculation of SUV, has less whole body radiation, and is performed in less time versus Octreoscan.
DNA-Repair Defects in Pancreatic Neuroendocrine Tumors and Potential Clinical Applications
Iris H. Liu,1 James M. Ford,2 Pamela L. Kunz.21Dartmouth College, Hanover, NH; 2Stanford University School of Medicine, Stanford, CA.
Background: While the role of DNA repair is not yet well understood in pancreatic neuroendocrine tumors (pNETs), the existing literature reveals important preliminary trends and targets in the genetic landscape of pNETs. Notably, pNETs have been shown to harbor defects in the direct reversal MGMT gene and the mismatch repair genes, suggesting that these genes may be strong candidates for further prospective studies.
Methods: PubMed searches were conducted for original studies assessing the DNA repair genes MGMT and MMR in pNETs, as well as for PTEN and MEN1, which are not directly DNA repair genes but are involved in DNA repair pathways. Searches were specific to pNETs, yielding five original studies on MGMT and four on MMR. Five original papers studied PTEN in pNETs. Three studied MEN1 in pNETs, and two others implicated MEN1 in DNA repair processes.
Results: The five studies on MGMT in pNETs found MGMT loss of between 24% and 51% by IHC staining and between 0% and 40% by promoter hypermethylation, revealing discrepancies in methods assessing MGMT expression as well as potential weaknesses in the correlation between MGMT IHC expression and promoter hypermethylation rates. Four studies on MMR in pNETs indicated similar ambiguities, as promoter hypermethylation of the MLH1 MMR gene ranged from 0% to 31% of pNETs. IHC staining revealed loss of MMR genes in between 0% and 36% of pNETs sampled. Studies also indicated that PTEN and MEN1 are commonly mutated genes in pNETs.
Conclusion: Further studies are essential in determining a more thorough repertoire of DNA repair defects in pNETs and the clinical significance of these defects. This literature review synthesizes the existing knowledge of relevant DNA repair pathways and studies of the specific genes that carry out these repair mechanisms in pNETs.
Long-Term Outcomes of Surgical Management of Pancreatic Neuroendocrine Tumors With Liver Metastases
Stefano Partelli,1 Marco Inama,2 Anja Rinke,3 Nehara Begum,4 Roberto Valente,2 Volker Fendrich,5 Martyn E. Caplin,6 Giuseppe Fusai,2 Massimo Falconi.11Pancreatic Surgery Unit, University Hospital of Ancona, Ancona, Italy; 2Hepato-pancreato-biliary and liver transplant surgery, Royal Free Hospital, London, United Kingdom; 3Department of Gastroenterology, University Hospital Marburg, Marburg, Germany; 4Department of Surgery, University of Lubeck, Lubeck, Germany; 5Department of Surgery, University Hospital Marburg, Marburg, Germany; 6Centre for Gastroenterology, Royal Free Hospital, London, United Kingdom.
Background: The value of surgical resection in the management of pancreatic neuroendocrine tumors (PNET) with liver metastases (LM) is still a matter of debate. Aim of the study was to evaluate the outcomes of surgical management of PNET with LM.
Methods: All patients with a diagnosis of stage IV PNET between 2000 and 2011 from four high-volume European Institutions, were retrospectively enrolled in the study. Patients were divided into 3 groups (R0 resection group, R1/R2 resection group, and no resection group). Univariate and multivariable analyses of predictors of progression-free survival (PFS) and overall survival (OS) were performed.
Results: We included 169 patients (94 males and 75 females) with a median age of 51 years. The majority of tumors were PNET G2 (57%) followed by PNET G1 (24%) and PNEC G3 (19%). LM were mainly bilobar (n=140, 83%). Overall 19 patients (11%) underwent R0 resection, 74 patients (44%) underwent R1/R2 resection, and 76 patients (45%) underwent only medical treatment. The median overall survival (OS) from diagnosis was 73 months. The 1-year, 2-year and 5-year OS rates were 92%, 80% and 59%. Patients who underwent R0 resection had a significantly better median OS from initial diagnosis compared with those who underwent R1/R2 resection and those who were conservatively treated (97 versus 89 versus 36 months, P=0.0001). On multivariate analysis, factors independently associated with OS from initial diagnosis were the presence of bilobar metastases (HR=2.724, 95%CI=1.378–5.383, P=0.004), PNEC-G3 (HR=6.138, 95% CI=2.816–13.378, P=0.0001) and R0 resection (HR=0.446, 95%CI= 0.268–0.741, P=0.002). Among 93 patients who underwent surgical resection, the presence of PNEC-G3 was the only factor independently associated with a poorer survival after surgery (median OS: 35 months versus 97 months, P<0.0001).
Conclusion: Radical surgical resection of PNET with LM is associated with a significant benefit although surgery should be reserved to well- or moderately differentiated forms.
A Prospective, Multi-Institutional Phase II Study of Pazopanib and Depot Octreotide in Advanced, Well-Differentiated Neuroendocrine Tumors
Alexandria T. Phan,*1 Daniel M. Halperin,*1 Jennifer A. Chan,2 David R. Fogelman,1 Kenneth R. Hess,3 Paige Malinowski,2 Eileen Regan,2 Chaan S. Ng,4 James C. Yao,1 Matthew H. Kulke.21Departments of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX; 2Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA; 3Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX; 4Diagnostic Radiology, University of Texas MD Anderson Cancer Center, Houston, TX.
Supported by: N01CM-2011-00039 (JCY)
Background: Treatment options for advanced well-differentiated neuroendocrine tumors (NET) remain limited. The mTOR inhibitor everolimus and the tyrosine kinase inhibitor sunitinib are active and approved for use in advanced pancreatic neuroendocrine tumors (pNET); no treatment has yet been approved for tumor control in patients with advanced carcinoid. Pazopanib is an orally bioavailable small molecule multitargeted kinase inhibitor inhibiting VEGF receptors 1, 2, and 3. We performed a prospective study of pazopanib with octreotide in patients with advanced NET.
Methods: We performed a two-cohort study in patients with advanced carcinoid or advanced pNET, using a 2-stage design. The primary endpoint was objective response rate (ORR), with secondary endpoints of progression-free survival (PFS), overall survival (OS), and toxicity.
Results: 52 patients (32 pNET and 20 carcinoid) were enrolled between 4/07 and 7/09. By intention to treat analysis, the pNET ORR was 21.9% (95% CI 11–38.8). There were no responses in the first stage of the carcinoid cohort, and accrual was terminated at 20 patients. Median PFS was 14.4 months in the pNET cohort and 12.2 months in the carcinoid cohort.
Conclusions: Treatment with pazopanib is associated with tumor regression and an encouraging PFS duration in patients with pNET. Further studies evaluating pazopanib in advanced pancreatic NET are warranted.
Trial Registration:www.clinicaltrials.gov Idenitifier: NCT00454363
Prognostic Significance of CDKN1B (p27) Expression in Gastroenteropancreatic Neuroendocrine Tumors
Zhi Rong Qian,1 Joshua M Francis,1,2 Monica Ter-Minassian,1,3 Jennifer A. Chan,1 Lauren K. Brais,1 Susanne M. Hooshmand,1 Nichole Brooks,1 Reiko Nishihara,1 Tingting Li,1,4 Yu Imamura,1 Mai Yamauchi,1 Kentaro Inamura,1 Sun A Kim,1 Kosuke Mima,1 Yasutaka Sukawa,1 Atsuhiro Masuda,1 Juhong Yang,1 Xihong Lin,5 David C. Christiani,2,6,7 Charles S. Fuchs,1,8 Matthew Meyerson,1,2 Shuji Ogino,1,6,9 Matthew H. Kulke.11Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; 2Broad Institute, Cambridge, MA; 3Department of Environmental Health, Chinese PLA General Hospital, Beijing, China; 4Department of Geriatric Gastroenterology, Chinese PLA General Hospital, Beijing, China; 5Department of Biostatistics, Harvard School of Public Health, Boston, MA; 6Department of Epidemiology, Harvard School of Public Health, Boston, MA; 7Massachusetts General Hospital, Harvard Medical School, Boston, MA; 8Channing Laboratory, Department of Medicine, Harvard Medical School, Boston, MA; 9Department of Pathology, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA.
Background: CDKN1B is a cyclin dependent kinase inhibitor that has been implicated in regulating tumor growth; loss of CDKN1B expression has been associated with poor prognosis in various human malignancies. Somatic mutations in CDKN1B have been reported in a subset (8%) of small intestinal NETs (SINETs). However, the clinical significance of expression and mutation of CDKN1B in patients with gastroenteropancreatic neuroendocrine tumors (GEP NETs) has not been defined.
Methods: We evaluated CDKN1B expression in 144 patients with GEP NETs and correlated expression levels with mutational status and with overall survival after adjusting for other clinical prognostic variables using Cox proportional hazards regression models. Immunohistochemical expression was scored according to the percentage of tumor nuclei expressing CDKN1B protein.
Results: Reduced expression (nuclear staining < 50%) of CDKN1B was detected in 18% (26/144) primary GEP NETs (19 /111 SINETs, 3/19 pancreatic NETs, and 4/15 other GEP NETs; respectively). Among 111 primary SI NETs, low expression of CDKN1B was associated with shorter overall survival (OS) (multivariate HR 2.72, p=0.017). In the cohort of patients with metastatic SINETs (n=75), low expression of CDKN1B was also associated with shorter OS (multivariate HR 2.87, p=0.016). Mutational status had previously been determined in 45 primary SINETS; of these, 5/45 had CDKN1B mutations. We did not observe a clear correlation between reduced CDKN1B expression and mutation of CDKN1B. However, mutation of CDKN1B (observed in 4/34 patients with metastatic SINETs) was potentially associated with worse OS (multivariate HR 3.48, p=0.065) in patients with metastatic SINETs.
Conclusion: Low expression, and potentially mutation, of CDNK1B appears to be associated with poor prognosis in gastroenteropancreatic neuroendocrine tumors.
Weight Gain After Acid Control in Zollinger Ellison Syndrome
Brian Riff,1 David A. Leiman,1 Douglas L. Fraker,2 Bonita Bennet,1 David C. Metz.11Division of Gastroenterology, Hospital of the University of Pennsylvania, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; 2Department of Surgery, Hospital of the University of Pennsylvania, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
Background: Zollinger Ellison Syndrome (ZES) is a disorder characterized by a gastroenteropancreatic neuroendocrine tumor, hypergastrinemia and gastric acid hypersecretion. Gastric acid hypersecretion produces ulcer disease, diarrhea and weight loss. No prior studies examined weight change after acid control.
Methods: We performed a retrospective cohort study of patients with ZES (n = 60) to examine changes in weight following medical or surgical control of acid hypersecretion. Appropriate dose PPI therapy was defined as a basal acid output (BAO) < 10 mEq/hr in patients with intact stomachs (< 5mEq/hr after acid-reducing surgery) or an absence of hypersecretory symptoms on at least twice daily full dose PPI. Weight changes expressed as change in percent change from baselines were examined at nadir weight, 6, 12, 18 and 24 months using single sample t-tests.
Results: Of the 60 patients, the primary cohort consisted of 47 patients that had a nadir weight recorded. The cohort consisted of 20 males; mean age = 57.9 + 14.4 yrs; mean weight 165 + 49.3 lbs; 14 (30%) with MEN1. Patient weights were significantly increased as a percent change above baselines following appropriate dose PPI therapy at 6 mo (6.4%), 12mo (6.9%), 18mo (11.9%) and 24mo (10.5%) (p < 0.005). This weight gain remained significant even in MEN-1 patients (p = 0.012). Surgical resection was performed on 17 patients (36.2%) with curative intent and 5 (29%) were considered biochemically cured. Significant weight gain was seen following surgical at 12mo (8%) and 18mo (7%) but that weight gain was lost at 24mo (0.8%, p = 0.78).
Conclusion: Our finding that effective acid control leads to weight gain in ZES patients is novel. Weight gain was most pronounced in surgically cured patients with sporadic disease. These results suggest that trending weight can be used as a surrogate for acid control in the appropriate patient population.
Phase I, Open-Label, Randomized, Pharmacokinetic/Pharmacodynamic (PK/PD) Study of Octreotide Subcutaneous (sc) Depot Versus Octreotide Long-Acting Repeatable (OCT-LAR) in Healthy Volunteers
John Roberts,1 Margareta Linden,2 Camilla Cervin,2 Fredrik Tiberg,2,3 Severine Sarp.41Novartis Pharmaceuticals Corporation, East Hanover, NJ; 2Camurus AB, Ideon Science Park, Lund, Sweden; 3Physical Chemistry, Lund University, Lund, Sweden; 4Oncology Clinical Development, Oncology Business Unit, Novartis Pharma AG, Basel, Switzerland.
Background: The LAR formulation of octreotide, the most widely used somatostatin analogue, must be reconstituted prior to intramuscular injection. Octreotide sc depot is a new ready-to-use formulation for sc administration. This phase I study compared the PK/PD of octreotide sc depot to OCT-LAR.
Methods: Healthy adult male/female volunteers received a single dose of octreotide sc 200 μg and were subsequently randomly assigned 1 week later to three injections of octreotide sc depot 30 mg/month (n=14) or OCT-LAR 30 mg/month (n=14). Blood samples were collected pre- and post-injection and at prespecified time points during the study. Adverse events (AEs) were recorded.
Results: Octreotide sc depot exhibited a steady, rapid increase to peak concentrations (Cmax) followed by a slow, exponential decrease through day 28. OCT-LAR displayed a burst concentration peak and rapid decline to undetectable values that rebounded by day 7, stabilized from day 10, and finally decreased around day 21. Relative bioavailability (using AUC28d) of octreotide sc depot versus OCT-LAR was 487% (90% CI: 411–578). Octreotide sc depot provided more rapid and greater IGF-1 suppression than OCT-LAR after injection during weeks 1–2, although IGF-1 levels remained similar during weeks 3–4; AUC for IGF-1 suppression was similar in both groups. In accordance with the known safety profile of octreotide, the most frequent AEs for both octreotide sc depot and OCT-LAR were mild to moderate gastrointestinal events. Local tolerability was generally good; local discomfort was mild and transitory when it did occur.
Conclusions: Octreotide sc depot provides greater octreotide bioavailability with a more rapid onset and similar duration of effect compared with OCT-LAR in healthy volunteers and offers enhanced convenience as it may be supplied in a convenient, prefilled syringe with a thinner needle. Phase III studies of octreotide sc depot in patients with neuroendocrine tumors and acromegaly are planned.
Previously presented at the 16th European Congress of Endocrinology (ECE); May 3–7, 2014; Warsaw, Poland.
Phase I, Open-Label, Randomized, Bioequivalence Study of Octreotide (OCT) Long-Acting Repeatable (LAR) Reconstituted in a New Vehicle (NV) vs OCT LAR 30 mg (Current Vehicle)
John Roberts,1 Katja Roessner,2 Antje Brueck-Scheffler,3 Anadya Tripathi Prakash,4 Severine Sarp.21Oncology Clinical Pharmacology, Novartis Pharmaceuticals Corporation, East Hanover, NJ; 2Oncology Clinical Development, Oncology Business Unit, Novartis Pharma AG, Basel, Switzerland 3Technical Research and Development, Novartis Pharma AG, Basel, Switzerland; 4Biostatistics and Data Management, Novartis Healthcare Pvt. Ltd, Hyderabad, India.
Background: OCT, a commonly prescribed somatostatin analog for the treatment of diarrhea and flushing associated with carcinoid syndrome, is available as an LAR formulation administered intramuscularly once every 4 weeks. SMS995L is a formulation in which OCT microparticles are reconstituted in an NV containing a surfactant that, in contrast to the current OCT LAR formulation, allows for shaking during the suspension process and inversion of the vial for withdrawal into the syringe prior to injection. The NV also allows for a reduced injection volume (2 mL) vs OCT LAR (2.5 mL) delivered via a smaller-diameter, safety-engineered needle (0.9 mm vs 1.1 mm), which is provided in the new injection preparation kit. This study was designed to confirm the bioequivalence of SMS995L 30 mg and OCT LAR 30 mg.
Methods: This was a single-dose, parallel, single-center study involving 2 treatment arms in healthy male volunteers. Over 14 weeks, the subjects underwent pharmacokinetic (PK) and safety assessments with a final visit at week 18.
Results: 106 subjects were randomized to OCT LAR (n=52) or SMS995L (n=54). The 90% confidence intervals for the ratios of geometric means comparing the primary PK parameters (Cmax, AUC0-d98, and AUC0-inf) after single-dose administration were within the predefined boundary (0.80, 1.25), thereby confirming the bioequivalence of the 2 formulations. Reported adverse events were consistent with the established safety profile of OCT LAR. Importantly, there were no relevant differences in the frequency of injection site reactions.
Conclusions: SMS995L 30 mg (OCT LAR in an NV) is bioequivalent to OCT LAR 30 mg (current vehicle), with no new safety signals observed. It is anticipated that the NV and the new injection preparation kit (vial adapter and a needle of smaller diameter) will enhance convenience and safety for the reconstitution and administration of OCT LAR.
Previously presented at the European Society for Medical Oncology (ESMO) Congress; September 26–30, 2014; Madrid, Spain.
Quality of Life (QoL) with Lanreotide Autogel/Depot (LAN) vs. Placebo in Patients with Enteropancreatic Neuroendocrine Tumors: Results From the CLARINET Core Study
Philippe Ruszniewski,1 Alexandria T. Phan,2 Martyn E. Caplin,3 Marianne E. Pavel,4 Jarosław B. Ćwikła,5 Markus Raderer,6 Eva Sedláčková,7 Guillaume Cadiot,8 Lucy Wall,9 Guido Rindi,10 Alison Langley,11 Edda Gomez-Panzani.121Beaujon Hospital, Clichy, France; 2Houston Methodist Hospital Cancer Center, Houston, TX; 3Royal Free Hospital, London, UK; 4Charité University Medicine Berlin, Berlin, Germany; 5University of Varmia and Masuria, The Faculty of Medical Sciences, Olsztyn, Poland; 6University Hospital, Vienna, Austria; 7First Faculty of Medicine and General Teaching Hospital, Prague, Czech Republic; 8Robert-Debré Hospital, Reims, France; 9Western General Hospital, Edinburgh, UK; 10Università Cattolica del Sacro Cuore, Rome, Italy; 11Ipsen, Les Ulis, France; 12Ipsen Biopharmaceuticals, Inc., Basking Ridge, NJ.
Background: QoL in patients with gastroenteropancreatic NETs can be affected by symptom burden, but also by treatment efficacy and safety. To better evaluate this, the EORTC developed a NET-specific QoL questionnaire (QLQ-GI.NET21) to be used in combination with its more generic questionnaire, EORTC QLQ-C30. Here, we examine the impact of LAN vs. placebo on QoL in patients in the CLARINET core study.
Methods: The CLARINET core study was a 96-week randomized double-blind phase III trial. Patients with metastatic well/moderately differentiated non-functioning enteropancreatic NETs were randomized to LAN 120 mg (n=101) or placebo (n=103) every 28 days, administered by deep subcutaneous injection (NCT00353496). The primary endpoint was progression-free survival (PFS). QoL, a secondary endpoint, was assessed at each study visit using the EORTC QLQ-C30 and the EORTC QLQ-GI.NET21. Safety was a key secondary endpoint.
Results: LAN significantly prolonged PFS vs. placebo (stratified log rank, p<0.001; hazard ratio 0.47 [95% CI: 0.30, 0.73]). Treatment-related AEs occurred in 50% of patients in the LAN group vs. 28% in the placebo group. Gastrointestinal disorders were the most common treatment-related AEs (37% vs. 19%). QLQ-C30 global health status and QLQ-GI.NET21 endocrine and gastrointestinal subscale scores were similar in the two treatment groups at baseline and throughout treatment, though inter-individual variation was high (Table). Results for other subscale scores of the QLQ-C30 and QLQ-GI.NET21 questionnaires were also similar between LAN and placebo.
Conclusions: Overall, patients receiving LAN 120 mg had a significantly improved PFS and a good safety/tolerability profile that did not compromise patients’ QoL vs. placebo. Further analyses are ongoing to evaluate QoL based on patient characteristics and treatment response.
Treatment Satisfaction, Symptom Control, and Quality of Life (QoL) With Lanreotide Autogel/Depot (LAN) in Neuroendocrine Tumor (NET) Patients With Carcinoid Syndrome (CS): Results From the SymNET Study
Philippe Ruszniewski,1 Martyn E. Caplin,2 Juan W. Valle,3 Catherine Lombard-Bohas,4 Graeme Poston,5 Petros Perros,6 Luboš Holubec,7 Gianfranco Delle Fave,8 Denis Smith,9 Patricia Niccoli,10 Pascal Maisonobe,11 Edda Gomez-Panzani.121Beaujon Hospital, Clichy, France; 2Royal Free Hospital, London, UK; 3Christie NHS Foundation Trust, Manchester, UK; 4Edouard-Herriot Hospital, Lyon, France; 5University Hospital Aintree, Liverpool, UK; 6Freeman Hospital, Newcastle-upon-Tyne, UK; 7Teaching Hospital Plzen, Plzen–Bory, Czech Republic; 8Ospedale Sant’ Andrea, Rome, Italy; 9Saint André Hospital, Bordeaux, France; 10CHU Timone, Marseille, France; 11Ipsen, Boulogne-Billancourt, France; 12Ipsen Biopharmaceuticals, Inc., Basking Ridge, NJ.
Background: CS associated with NETs can have a negative impact on patients’ QoL. Here, QoL data are evaluated from the SymNET study.
Methods: The SymNET study was a large observational trial involving patients with a NET and a history of CS-related diarrhea (NCT01234168). Patients had been treated with LAN for >3 months. Patient-reported outcomes were assessed at a routine clinic visit. The primary endpoint was patient satisfaction with diarrhea control (PSD). Symptoms were evaluated using medical records. QoL was assessed using the EORTC QLQ-C30 and QLQ-GI.NET21 questionnaires, which assess functional dimensions (QLQ-C30; higher scores = better QoL) and symptoms (QLQ-C30 and QLQ-GI.NET21; lower scores = better QoL). Overall QoL was evaluated according to satisfaction with CS symptom control.
Results: Among 273 patients enrolled, 76% [95% CI: 70, 81] were ‘completely’ or ‘rather’ satisfied with diarrhea control. There was a clinically significant reduction in stool number and statistically significant improvements in urgency, leakage, and associated pain since the initiation of LAN. Scores for the QLQ-C30 global health status were high (mean [SD] 65.5 [22.1], median [range] 66.7 [0–100]), while scores for the QLQ-GI.NET21 endocrine and gastrointestinal subscales were low (endocrine, mean [SD] 19.4 [21.3], median [range] 11.1 [0–100]; gastrointestinal, mean [SD] 22.9 [17.8], median [range] 20.0 [0–87]). Patients who expressed a high PSD scored well on their overall rating of QoL (see Table 1); in total, 70% of patients who were ‘rather’ or ‘completely’ satisfied had ‘good’, ‘very good’, or ‘excellent’ QoL.
Conclusion: In a real-world setting, CS symptom control with LAN treatment translates into favorable levels of satisfaction among patients with NETs. Higher satisfaction levels were consistent with higher global health QoL scores.
Ki 67 and/or Mitotic Count in the Czech Neuroendocrine Tumour Registry
Eva Sedlackova,1 Jaroslava Barkmanova,1 Hana Honova,1 Jiri Tomasek,2 Hana Siffnerova,3 Vaclav Mandys,4 Denisa Maluskova,5 Jan Muzik.51Dept. of Oncology, 1st Medical Faculty and General Faculty Hospital Prague, Czech Republic; 2Masaryk Memorial Cancer Institute Brno, Czech Republic; 3Dept. of Oncology, Hospital Ceske Budejovice, Czech Republic; 4Dept. of Pathology, 3rd Medical Faculty, Hospital Kralovske Vinohrady Prague, Czech Republic; 5Institute of Biostatistics and Analysis, Masaryk University Brno, Czech Republic.
Background: The aim of this study is correlation of proliferation index Ki-67 and/or mitotic count (MC) in a group of gastroenteropancreatic and lung neuroendocrine neoplasmas in the Czech Neuroendocrine Tumour Registry with median overall survival of the patients according to the origin of the primary tumour, regardless to the stage of the disease.
Methods: In April 2014, data of 1151 patients in the Czech Neuroendocrine Registry have been collected from hospital records, including demography, details of histology, staging, treatment and its outcome. 802 patients had information about Ki 67 and/or MC status. They were divided into 3 groups: Ki-67/MC < 2, Ki-67/MC 2–20, Ki-67/MC >20. The retrospective analysis of proliferation index/mitotic count influence on median overall survival (OS) according to the origin of the primary tumor was done.
Results: 316 pts (39.4%) had Ki 67/MC< 2, 385 pts (48%) had Ki 67/MC between 2–20 and 101 pts (12.6%) had Ki 67/MC > 20. According to topography Ki 67/MC < 2 was most frequent in colorectal NENS, Ki 67/MC between 2–20 was most frequent in stomach, small bowel and pancreatic NENS. The highest frequency of Ki67/MC > 20 was in lung and pancreatic NENS. Median overall survival in all patients with Ki 67/MC > 20 was 2.0 years (1.5; 2.6), in two other groups was not reached. Individual figures for small bowel, lung and pancreatic NENS strongly support the influence of Ki-67/MC on median OS.
Conclusion: Ki-67 index/MC is an essential predicting parameter. Findings from the Czech Neuroendocrine Registry confirmed the highest frequency of Ki67/MC > 20 in lung and pancreatic NENs. Median OS in this group of patients in lung was 2.7 years (0.0; 5.8), median OS in pancreatic NENs 1.4 year (0.6; 2.1) in contrast to groups with Ki-67< 20, where median overall survival was not reached.
Octreotide LAR Among Elderly Patients With Neuroendocrine Tumors: A Survival Analysis of SEER-Medicare Data
Chan Shen,1 Ya-Chen Tina Shih,2 Ying Xu,3 James C. Yao.41University of Texas MD Anderson Cancer Center, Departments of Health Services Research and Biostatistics, Houston, TX; 2University of Chicago, Department of Medicine, Chicago, IL; 3University of Texas MD Anderson Cancer Center, Department of Health Services Research, Houston, TX; 4University of Texas MD Anderson Cancer Center, Department of Gastrointestinal (GI) Medical Oncology, Houston, TX.
Background: Octreotide long-acting repeatable (LAR) is approved in the US for the management of carcinoid syndromes among patients with neuroendocrine tumors (NETs). The objective of our study was to evaluate the impact of octreotide LAR on overall survival (OS) as it has not been established.
Methods: NET patients diagnosed between 1/1999 and 12/2009 were identified from the SEER-Medicare database. Those under age 65, with histologic grade 3, 4 or unknown, enrolled in HMOs, or without continuous enrollment in Medicare Parts A and B were excluded. We compared the OS of NET patients who started octreotide LAR within 12 months of diagnosis to those who did not receive it during the same period. We conducted Kaplan-Meier estimations and Cox proportional hazard models to examine the association between octreotide LAR and OS.
Results: Among 1,176 distant stage patients, 233 (20%) received octreotide LAR within 12 months of diagnosis, compared to 2% (96 in 5,764) of local/regional stage patients. Median OS for patients who started octreotide LAR within 12 months was 35.22 months [95%CI, 27.96 – 47.77], longer than those who did not receive it (19.15 months [95%CI, 16.36 – 22.80]; P<0.0001). Multivariate analysis showed that octreotide LAR was associated with significant survival improvement for distant stage patients (HR=0.68, P<0.001) and in the subgroups with (HR=0.65, P=0.003) and without (HR=0.55, P=0.002) carcinoid syndrome. No survival benefit was found among local/regional stage patients.
Conclusions: This population-based study suggests potential survival benefits of octreotide LAR among elderly distant stage NET patients, both with or without carcinoid syndrome.
Pancreastatin Predicts Survival in Neuroendocrine Tumors
Scott K. Sherman,1 Jessica E. Maxwell,1 M. Sue O’Dorisio,2 Thomas M. O’Dorisio,3 James R. Howe.11Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA; 2Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA; 3Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA.
Background: Serum neurokinin A, chromogranin A, serotonin, and pancreastatin reflect tumor burden in neuroendocrine tumors. We sought to determine whether their levels correlate with survival in surgically managed small bowel (SBNETs) and pancreatic neuroendocrine tumors (PNETs).
Methods: Clinical data were collected with Institutional Review Board approval for patients undergoing surgery at one center. Progression-free (PFS) and overall (OS) survival were from the time of surgery. Event times were estimated by the Kaplan–Meier method. Preoperative and postoperative laboratory values were tested for correlation with outcomes. A multivariate Cox model adjusted for confounders.
Results: Included were 98 SBNETs and 78 PNETs (see Figure 1). Median follow-up was 3.8 years; 62 % had metastatic disease. SBNETs had lower median PFS than PNETs (2.0 vs. 5.6 years; p < 0.01). Median OS was 10.5 years for PNETs and was not reached for SBNETs. Preoperative neurokinin A did not correlate with PFS or OS. Preoperative serotonin correlated with PFS but not OS. Higher levels of preoperative chromogranin A and pancreastatin showed significant correlation with worse PFS and OS (p < 0.05). After multivariate adjustment for confounders, preoperative and postoperative pancreastatin remained independently predictive of worse PFS and OS (p < 0.05) (Figure 1). Whether pancreastatin normalized postoperatively further discriminated outcomes. Median PFS was 1.7 years in patients with elevated preoperative pancreastatin versus 6.5 years in patients with normal levels (p < 0.001). Patients with elevated preoperative pancreastatin had a 5-year OS rate of 72.6% versus 88.3% in those with normal levels (p=0.04).
Conclusion: Higher pancreastatin levels are significantly associated with worse PFS and OS in SBNETs and PNETs. This effect is independent of age, primary tumor site, and presence of nodal or metastatic disease. Pancreastatin provides valuable prognostic information and identifies surgical patients at high risk of recurrence who could benefit most from novel therapies.
Efficacy of Octreotide Long-Acting Repeatable (OCT) From the Phase III RADIANT-2 Study in Patients With Advanced Neuroendocrine Tumors (NET): A Post-Hoc Analysis of the Placebo (PBO) Arm With Updated Survival Data
Jonathan R. Strosberg,1 James C. Yao,2 Emilio Bajetta,3 Mounir Aout,4 Bert Bakker,5* John D. Hainsworth,6 Philippe B. Ruszniewski,7 Eric Van Cutsem,8 Kjell E. Öberg,9 Marianne E. Pavel.101Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL; 2Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine; The University of Texas MD Anderson Cancer Center, Houston, TX; 3Istituto di Oncologia, Policlinico di Monza, Monza, Italy; 4Novartis Pharma AG, Basel, Switzerland; 5Novartis Pharmaceuticals Corporation, East Hanover, NJ; 6Sarah Cannon Research Institute, Nashville, TN; 7University of Paris VII and Hopital Beaujon, Paris, France; 8Digestive Oncology Unit, University Hospital Gasthuisberg/Leuven, Leuven, Belgium; 9Uppsala University Hospital, Uppsala, Sweden; 10Department of Hepatology and Gastroenterology, Charité Universitätsmediz in Berlin/Campus Virchow Klinikum, Berlin, Germany. *Current affiliation: Versartis, Menlo Park, CA.
Background: OCT demonstrated antitumor activity and significantly extended time to tumor progression (TTP) vs PBO in patients with metastatic midgut NET (PROMID trial, Rinke et al. 2009). The RADIANT-2 study evaluated patients with symptomatic advanced NET. Here we report a post-hoc analysis assessing progression free survival (PFS) and overall survival (OS) of OCT (30 mg q28d) in the PBO+OCT arm of this study for the overall population and patients with midgut NET.
Methods: Patients eligible for the RADIANT-2 study had progressive disease within the past 12 months and a history of carcinoid symptoms (diarrhea or flushing). PFS (by central review as per RECIST 1.0, cutoff, April 2, 2010) and OS (cutoff, June 13, 2013) in the PBO+OCT arm were estimated by prior somatostatin analogue (SSA) use and primary tumor location subgroups using the Kaplan-Meier method.
Results: 213 patients were randomized to PBO+OCT. Of these, 47 (22%) were SSA naive (foregut, 32%; midgut, 51%; hindgut, 4%; not classified or missing, 13%) and 166 (78%) had received SSA (foregut, 10%; midgut, 72%; hindgut, 11%; not classified or missing, 7%) prior to study entry. Median PFS and OS findings are presented in Table 1.
Conclusions: This post-hoc analysis, for the first time, provides prospective data on survival outcomes of patients with progressive NET treated with SSA therapy. SSA-naive patients with progressive midgut NET treated with OCT had a relatively long median PFS of 22.2 months, exceeding the TTP of 14.3 months observed in the PROMID study (World Health Organization criteria). This data may represent a more accurate reflection of PFS by RECIST associated with first-line SSA use in midgut NET.
Real-World First-Line Treatment Patterns Among US Carcinoid Syndrome Patients
Gordon H. Sun,1 Maureen P. Neary,2 Eunice Chang,1 Michael S. Broder.11Partnership for Health Analytic Research, LLC, Beverly Hills, CA; 2Novartis Pharmaceuticals Corporation, East Hanover, NJ.
Background: Initial systemic therapy for carcinoid syndrome (CS), a condition caused by active neuroendocrine tumors, often consists of somatostatin analogues such as octreotide. However, treatment patterns in real-world practices have not been well described.
Methods: We conducted a retrospective cohort study using MarketScan® data from 1/1/2003 - 12/31/2012. Newly diagnosed CS patients had 1 medical claim for CS (ICD-9-CM code 259.2) plus either ≥1 additional claim for CS or ≥1 for carcinoid tumors (ICD-9-CM 209.x), and had no evidence of CS for 1 year prior to index CS diagnosis. Among these patients, we identified those who received a pharmacologic agent as first treatment, including octreotide LAR, octreotide SA, lanreotide, cytotoxic chemotherapy (doxorubicin, fluorouracil, cisplatin, etoposide, temozolomide, streptozocin), and other drugs (everolimus, sunitinib, interferon). A graphical program was used to describe treatment patterns for each patient. Time period of observation for some may be limited by early disenrollment in the database.
Results: There were 2,822 newly diagnosed patients with CS in any diagnostic field; 885 received a pharmacologic agent as first treatment. Of these, 487 (55.0%) received octreotide LAR, 228 (25.8%) received octreotide SA, 139 (15.7%) received cytotoxic chemotherapy, and the remainder received a combination of the above agents or other drugs. Figure 1 demonstrates detailed treatment patterns with observational periods lasting from <1 year up to 10 years. First-line octreotide LAR may be used continuously for up to 7 years; in certain patients who used first-line octreotide SA, subsequent use of octreotide LAR lasted as long as 9 years.
Conclusion: A substantial proportion of CS patients who received octreotide LAR as first-line pharmacologic therapy or after initial, short-duration treatment with octreotide SA remained on octreotide LAR for multiple years. Additional research should review treatment duration in real-world clinic settings alongside clinical and healthcare utilization outcomes.
The Healthcare and Economic Impact of Diarrhea on US Patients With Carcinoid Syndrome
Michael S. Broder,1 Gordon H. Sun,1 Maureen P. Neary,2 Eunice Chang.11Partnership for Health Analytic Research, LLC, Beverly Hills, CA; 2Novartis Pharmaceuticals Corporation, East Hanover, NJ.
Background: Carcinoid syndrome (CS) is caused by neuroendocrine tumors actively secreting serotonin; one of the most common symptoms is diarrhea. The healthcare and economic burden of diarrhea in CS patients has not been previously quantified.
Methods: We conducted a retrospective cohort study using MarketScan® from 1/1/2003 to 12/31/2012. Newly diagnosed CS patients had 1 medical claim for CS (ICD-9-CM code 259.2) plus ≥1 additional claim for either CS or carcinoid tumors (ICD-9-CM 209.x), in any diagnostic field. All patients were disease-free for 1 year prior to CS diagnosis and were followed for 1 year. Non-infectious diarrhea was identified using ICD-9-CM 564.5 and 787.91. We compared healthcare resource utilization (HRU) and costs within 1 year of CS diagnosis among patients with and without diarrhea.
Results: There were 2,822 newly diagnosed patients with CS in any diagnostic field. Overall mean age was 51.5 years and 56.9% were women. Patients had a mean Charlson Comorbidity Index of 3.6. In this cohort, 534 (18.9%) of whom had ≥1 claim associated with diarrhea.
Patients with diarrhea more commonly had ≥1 hospitalization (49.6% vs. 39.6%, p<.001) or ≥1 ED visit (13.4% vs. 9.2%, p<.001), as well as more office visits (25.5 vs. 18.7, p<.001), compared to those without diarrhea. Mean duration of hospitalization of patients with diarrhea was longer than in those without diarrhea (11.6 vs. 8.0, p<.001). Similar trends were observed among HRU claims with a CS- or carcinoid tumor-related primary diagnosis. Patients with diarrhea accrued 58.9% higher annual total costs than those without diarrhea ($82,032 vs. $51,621, p<.001).
Conclusion: The burden of illness in newly diagnosed CS patients with diarrhea is significantly higher than in those without the diagnosis. Further research is needed to better understand the drivers of costs in patients with severe diarrhea and costs related to complications from diarrhea.
Preoperative Metyrosine Improves Cardiovascular Outcomes for Patients Undergoing Surgery for Pheochromocytoma and Paraganglioma
Heather Wachtel,1 Isadora Cerullo,1 Edmund K. Bartlett,1 Lauren Fishbein,2 Robert E. Roses,1 Douglas L. Fraker,1 Debbie L. Cohen.31Department of Surgery; 2Department of Medicine, Division of Endocrinology, Diabetes and Metabolism; 3Department of Medicine, Division of Renal, Electrolyte, and Hypertension, Hospital of the University of Pennsylvania, Philadelphia, PA.
Background: The goal of preoperative pharmacotherapy for pheochromocytoma and paraganglioma (PHEO/PGL) resection is to minimize intraoperative hemodynamic instability and perioperative cardiovascular complications, but no randomized control trials exist to compare regimens. We analyzed our series of resections to determine the impact of metyrosine on operative outcomes.
Methods: Consecutive patients who underwent resection for PHEO/PGL (2000–2014) were identified. Retrospective chart review was performed. Patients received either phenoxybenzamine alone (PA) or metyrosine and phenoxybenzamine (MP). Univariate analysis was performed. Primary outcome was hemodynamic abnormality, defined as heart rate (HR) >100 bpm or systolic blood pressure (SBP) >140 mmHg. Secondary outcome was perioperative cardiovascular complication, defined as CVA, TIA, MI, cardiac arrest, or arrhythmia within 30 days of operation.
Results: Of 163 patients, 88.3% (n=144) were MP, and 11.7% (n=19) were in the PA group. There were no significant preoperative differences between the cohorts in terms of demographics, blood pressure control, or anti-hypertensive medications. The groups had comparable intraoperative parameters including operative duration (145 vs. 127 min, p=0.148), blood loss (150 vs. 200 ml, p=0.393), and intraoperative resuscitation with intravenous fluids (24.2 vs. 27.7 ml/min, p=0.198), anti-hypertensive medications (84.0 vs. 79.0%, p=0.583) and vasopressors (75.6 vs. 79.0%, p=0.748). There were no significant differences between groups in hemodynamic abnormality by HR criteria (12.1 vs. 5.3%, p=0.377) or SBP criteria (12.9 vs. 10.5%, p=0.773). Although the overall complication rate was comparable between the cohorts (23.2 vs. 42.1%, p=0.076), PA patients had an almost 8-fold increase in cardiovascular complications (15.8 vs. 2.2%, p=0.004), and a significantly longer median length of stay (6.0 vs. 4.0 days, p=0.010).
Conclusions: While preoperative metyrosine did not impact intraoperative hemodynamic stability, it significantly decreased perioperative cardiovascular complication rates and length of hospitalization in patients undergoing PHEO/PGL resection. This data suggests that the addition of preoperative metyrosine to phenoxybenzamine may be beneficial.
Adjuvant Intraoperative Post-Dissection Tumor Bed Chemotherapy: A Novel Approach in Treating Midgut Neuroendocrine Tumors
Yi-Zarn Wang,1 Aman Chauhan,2 Michael A. Hall,3 J. Philip Boudreaux,1 Eugene Woltering,1 Lowell Anthony.41Department of Surgery, Section of Surgical Oncology and Surgical Endocrinology, LSUHSC Kenner, LA; 2Department of Internal Medicine and Pediatrics, LSUHSC New Orleans, New Orleans, LA; 3Department of Surgery, LSUHSC New Orleans, New Orleans, LA; 4Department of Medical Oncology, University of Kentucky, Lexington, KY.
Background: Midgut neuroendocrine tumor (NET) patients are often diagnosed at an advanced stage with extensive mesenteric lymph node and liver metastasis. Even with skillful surgical dissection, macro and microscopic residual disease at the dissection site remains a possibility. We hypothesized these potential tumor residuals in mesenteric lymph node dissection beds can be eliminated safely by a local application of 5-fluouracil (5-FU).
Methods: Retrospectively, charts of 62 consecutive midgut NET patients with boggy mesenteric lymphadenopathy underwent cytoreductive debulking surgeries from 1/2007 to 12/2009 were reviewed. 32 patients received an intraoperative application of 5-FU saturated gelfoam strips secured into the mesenteric defect following the extensive lymphadenectomy. 30 untreated patients served as a control.
Results: 5-year survival after cytoreductive surgeries was 22/32 (68.8%) for the treated group, versus 20/30 (66.7%) for the control. 6 patients (6/32, 18.8%) among the study group required additional debulking surgeries, versus 16 patients (16/30, 53.3%) in the controlled group. Upon reoperation, locoregional recurrence was noted in 9 of the 16 patients (56.3%) in the control group, versus only 2/6 (33.3%) of treated patients. Post-op complication rates are similar in the two arms.
Conclusion: Intraoperative application of chemotherapy is a safe and effective adjuvant for eliminating any potential microscopic residual disease after extensive cytoreductive surgeries in advanced stage NET patients with mesenteric lymph node metastasis. It provides patients with sustained, slow releasing, high dose of 5-FU within the surgical bed with a negligible side effect profile, whereby reducing local recurrence rates and decreased the need of reoperation. Further study is required to evaluate its effect on long term survival.
In Vitro Chemotherapy Profiling of Well-Differentiated Midgut Neuroendocrine Tumors (NETs) Based on Individual Patient Tumor Biomarkers Analysis
Yi-Zarn Wang,1 Aman Chauhan,2 Jean P. Carrasquillo,3 Alexis Carimi,3 Elizabeth McCord,3 Maria M. Chester,3 Robert A Ramirez,4 Eugene Woltering,1 J. Philip Boudreaux,1 Daniel Raines,5 Lowell Anthony.61Department of Surgery, Section of Surgical Oncology and Surgical Endocrinology, Kenner, LA; 2Department of Internal Medicine and Pediatrics, LSUHSC New Orleans, New Orleans, LA; 3Department of Surgery, LSUHSC New Orleans, New Orleans, LA; 4Department of Medicine, Section of Hematology and Oncology, LSUHSC, New Orleans, New Orleans, LA; 5Department of Medicine, Section of Gastroenterology, LSUHSC New Orleans, New Orleans, LA; 6Department of Medical Oncology, University of Kentucky, Lexington, KY.
Background: Midgut neuroendocrine tumors (NETs) are rare malignancies with indolent clinical courses. In general, they are well differentiated with most tumor cells in the G0 phase of the cell cycle, consistent with the poor response rate of NETs to chemotherapy in vivo. We hypothesize that insults, such as surgery, can drive NET cells from G0 into S phase and that biomarker analysis of individual patient tumors harvested and grown in the lab will provide useful practical guide for future intra and post operative adjuvant therapy.
Methods: 97 well-differentiated midgut NET patients underwent cytoreductive surgery at our institution between 5/2012 and 10/2012. 148 surgical specimens were collected and submitted to a single commercial lab for processing. Primary tumors, lymph nodes and liver metastases were harvested and cultured. Their RNAs were then extracted to analyze the expressivity a total of 88 different biomarkers. Based on our patients specific tumor biomarker expressivity and known correlations between 36 anti-neoplastic agents with their linked biomarkers, recommendations were reported as clinically benefit or lacking such benefit.
Results: A total of 148 specimens from 97 patients were tested. In four of the 97 patients, no clinically beneficial chemotherapy agent could be identified. Among the remaining 93 patients, the top three agents that are most likely to be clinically beneficial are: Fluorouracil, Cisplatin and Carboplatin. These were reported to be clinically beneficial in 135/148 (91.2%), 103/148 (69.6%), and 103/148 (69.6%) patients respectively.
Conclusions: Midgut NETs are slow growing tumors which are chemotherapeutically inert owing to the fact that most of the tumor cells are in G0 cell cycle. Surgical insult drives NET cells into active synthetic phase where they begin to express biomarkers specific to their tumor cells. Analysis of these biomarkers guides further potential beneficial therapy based on the current known associations among biomarkers and chemotherapy agents. These results must then be compared and confirmed against a direct in-vitro chemo sensitivity assessment conducted simultaneously on the same patients.
Reappraisal of Lymphatic Mapping for Midgut Neuroendocrine Patients Undergoing Cytoreductive Surgery
Yi-Zarn Wang,1 Jean P Carrasquillo,1 Elizabeth McCord,1 Rhea Vidrine,1 Monica L. Lobo,1 S. Ali Zamin,1 Philip Boudreaux,1 Eugene Woltering.11Division of Surgical Oncology, Department of Surgery, LSUHSC New Orleans, New Orleans, LA.
Background: We previously reported that midgut NETs often develop alternative lymphatic drainage due to lymphatic obstructions from extensive mesenteric lymphadenopathy thus making intraoperative lymphatic mapping mandatory. We hypothesize that this innovative approach needs a longer term validation.
Methods: We updated our results by reviewing 303 patients who underwent cytoreduction from November 2006 to October 2011. Of these patients, 112 had lymphatic mappings and 98 were for midgut NET primaries. Among them, seventy-seven (77) mappings were for the initial cytoreduction and 35 were for re-exploration and further cytoreduction. The operative findings, pathology reports and long-term surgical outcomes were reviewed.
Results: Lymphatic mapping changed traditional resection margins in 92% of patients. Of the 35 patients who underwent re-exploration without initial mapping, 19 (54%) showed a recurrence at or near the anastomotic sites. In contrast, none of the112 mapped patients had shown signs of recurrence in a 1–5 year follow-up. Additionally, 20/45 (44.4%) ileocecal valves were spared in patients whose tumors were at the terminal ileum which, traditionally, would call for a right hemicolectomy.
Conclusions: With a longer follow up, lymphatic mapping have proven to be a safe and effective way to prevent local recurrences and preserve the ileocecal valve for selected patients.
Telotristat Etiprate (TE) in a Subset of Patients With Carcinoid Heart Disease Included in Two Phase 2 Trials for Carcinoid Syndrome
Darren Wheeler,1 Matthew Kulke,2 Thomas O’Dorisio,3 Dieter Hörsch,4 Shanna Jackson,1 Gui-Lan Ye,1 Hyung-Woo Kim,1 Brian Zambrowicz,1 Arthur Sands A,1 Douglas Fleming.11Lexicon Pharmaceuticals, Inc., The Woodlands, TX; 2Dana-Farber Cancer Institute, Boston, MA; 3University of Iowa Hospitals and Clinics, Iowa City, IA; 4Zentralink Bad Berka GmbH, Bad Berka, Germany.
Background: Serotonin is a key mediator of carcinoid syndrome (CS). High levels of urinary 5-hydroxyindoleacetic acid (u5-HIAA, a serotonin metabolite) have also been linked with carcinoid heart disease (CaHD). Telotristat etiprate, a novel, oral inhibitor of serotonin synthesis, is in Phase 3 development for the treatment of CS. There is limited information on the potential benefits of serotonin reduction in patients with CaHD.
Methods: We retrospectively reviewed data on all patients who received telotristat etiprate in Phase 2 trials for CS. In patients with prior history of CaHD, we assessed baseline characteristics, reductions in u5-HIAA, adverse events, and procedures while on telotristat etiprate.
Results: Of the 38 enrolled patients, 5 patients (13%) had a history of CaHD and were evaluable. All had elevated baseline u5-HIAA levels (mean 144 mg/24 hours, range: 10–282), despite use of somatostatin analogs (SSAs) (5/5 patients) and prior tumor-directed therapies (4/5 patients). In all patients, levels of u5-HIAA decreased over time (mean maximum reduction 82%, range: 78–86%). As of Oct 2013, mean duration of telotristat etiprate exposure was 71 weeks (range: 12–164 weeks); 2 patients remain in the study, with >128 weeks exposure at the highest dose of telotristat etiprate (500 mg tid), including 1 patient who received a pulmonary valve replacement ∼2 years ago. There were 4 serious adverse events (including 2 heart valve surgeries), none of which were considered drug-related.
Conclusions: In 5 patients with CaHD, u5-HIAA levels decreased substantially while on telotristat etiprate. Additional studies are warranted.
Telotristat Etiprate in a Subset of Carcinoid Syndrome Patients Who Have High Levels of Urinary 5-hydroxyindoleacetic Acid and Frequent Flushing
Darren Wheeler,1 Dieter Hörsch,2 Juan Valle,3 Pablo Lapuerta,1 Brian Zambrowicz,1 Arthur Sands,1 Douglas Fleming.11Lexicon Pharmaceuticals, Inc, The Woodlands, TX; 2Zentralink Bad Berka GmbH, Bad Berka, Germany; 3The University of Manchester / The Christie NHS Foundation Trust, Manchester, Department of Medical Oncology, Manchester, UK
Background: Serotonin is a key mediator of carcinoid syndrome (CS), which includes gastrointestinal symptoms and flushing. High levels of urinary 5-hydroxyindoleacetic acid (u5-HIAA, a serotonin metabolite) have been linked with carcinoid heart disease (CaHD). Additionally, CS patients having >3 flushing episodes/day have a 5-fold risk of developing CaHD. Telotristat etiprate is an oral inhibitor of serotonin synthesis in Phase 3 development for the treatment of CS. There is limited information on the potential benefits of serotonin reduction in patients who may be at higher risk for CaHD.
Methods: We retrospectively reviewed data on all patients who received telotristat etiprate in a Phase 2 trial for CS. In patients with identified risk factors for developing CaHD (elevated u5-HIAA and >3 flushing episodes/day), we assessed baseline characteristics, reductions in u5-HIAA, improvements in daily bowel movements (BMs), and flushing frequency, as well as adverse events while on telotristat etiprate.
Results: Of the 15 enrolled patients, 5 patients (33%) met the criteria and had complete 12-week data available, including a patient diagnosed with CaHD 1 month before entering study. At baseline, these 5 patients had elevated u5-HIAA levels (mean 97 mg/24 hrs, range 11 to 282 mg/24 hrs) despite use of somatostatin analogs (SSAs) (3/5 patients), as well as inadequately controlled CS (≥4 daily BMs and ≥3 episodes of flushing/day). At week 12, u5-HIAA levels were reduced (mean reduction 67%, range 44 to 97%). There was also reduction in BM frequency (mean reduction 52%, range 32 to 72%) and daily flushing (mean reduction 45%, range −3 to 86%), see Table 1. There was 1 SAE of gastroenteritis, not considered drug-related.
Conclusions: In CS patients with CaHD or at risk for CaHD, u5-HIAA levels, flushing, and BM frequency all decreased substantially within 12 weeks of telotristat etiprate treatment.
Phase 1 Expansion Study of an Oral TORC1/TORC2 Inhibitor (CC-223) in Non-Pancreatic Neuroendocrine Tumors (NET)
Edward Wolin,1 Monica Mita,1 Tim Meyer,2 Johanna Bendell,3 Amit Mahipal,4 John Nemunaitis,5 Pam Munster,6 Luis Paz-Arez,7 Wayne Hull,8 Angela James,9 Torsten Trowe,10 Mahesh Swaminathan,11 Xiaoling Wu,11 Hans de Haan.101Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA; 2University College Hospital, London, UK; 3SCRI/Tennessee Oncology, PLLC, Nashville, TN; 4H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; 5Mary Crowley Cancer Research Center, Dallas, TX; 6UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; 7Hospital Universitario Virgen del Rocío, Seville, Spain; 8Celgene Corporation, Basking Ridge, NJ; 9Celgene Corporation, Summit, NJ; 10Celgene Corporation, San Francisco, CA; 11Celgene Corporation, Berkeley Heights, NJ.
Background: Clinical efficacy of everolimus, an allosteric TORC1-selective inhibitor, has been established in pancreatic NET. CC-223, an ATP-competitive inhibitor of the mTOR kinase, inhibits both TORC1 and TORC2 complexes.
Methods: Subsequent to MTD determination, non-pancreatic NET subjects enrolled in two expansion cohorts using CC-223 starting doses of 45 or 30 mg QD, administered in 28-day cycles until disease progression.
Results: Preliminary results on June 16, 2014 are reported for both dosing cohorts combined. Forty-seven subjects with progression within the prior 12 months while receiving somatostatin analogs (SSA) were treated. The majority of tumors (58%) were midgut with liver metastases; 30/43 (64%) subjects had refractory carcinoid syndrome despite SSA use. The most common (> 20%) related adverse events were diarrhea, stomatitis and fatigue (70% each), rash (65%), nausea (43%), pruritus (39%), hyperglycemia (30%), anorexia (26%), thrombocytopenia and xerostomia (22% each). Dose reduction (30, 20 or 15 mg QD) was required for 74% subjects, usually during cycle 1 or 2; thereafter treatment was well tolerated. Inhibition of TORC1 and TORC2 biomarkers was confirmed in blood cells. Although not prospectively collected, 12/15 (80%) subjects with carcinoid reported marked reduction of flushing and 11/20 (49%) had reduced bowel movements. Symptomatic improvement generally occurred early and persisted despite dose reduction. 9/23 (39%) subjects showed ≥50% reduction in NET-related hormone levels elevated at baseline. Reduction in FDG-PET glucose uptake (≥ 25% SUV) at day 15 was observed in 18/34 (53%) paired scans. Best tumor response (RECIST1.1) in 39 subjects with restaging CTs included stable disease in 35, partial response in 3 and progressive disease in 1. Median treatment duration was 8 cycles (range 1–25 cycles) with a 6-month PFS rate of 85% (68%, 94%).
Conclusions: Encouraging signals of biomarker and clinical activity were observed in NET, including prolonged stable disease in the majority of subjects and symptomatic improvement in those with refractory carcinoid syndrome.
Everolimus (EVE) for the Treatment of Advanced Pancreatic Neuroendocrine Tumors (pNET): Final Overall Survival (OS) Results of a Randomized, Double-Blind, Placebo (PBO)-Controlled, Multicenter Phase 3 Trial (RADIANT-3)
James C. Yao,1 Marianne Pavel,2 Catherine Lombard-Bohas,3 Eric van Cutsem,4 Du Lam,5 Tiffany Kunz,5 Ulrike Brandt,6 Jaume Capdevila,7 Elisabeth G.E. De Vries,8 Paola Tomassetti,9 Timothy Hobday,10 Rodney Pommier.111Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; 2Charité Universitätsmedizin, Berlin, Germany; 3Hôpital Edouard Herriot, Lyon Cedex, France; 4University Hospital Gasthuisberg, Leuven, Belgium; 5Novartis Pharmaceutical Corporation, East Hanover, NJ; 6Novartis Pharma AG, Basel, Switzerland; 7Vall d’Hebron University Hospital, Barcelona, Spain; 8University Medical Center Groningen, Groningen, Netherlands; 9Masarykuv Onkologicky Ustav, Brno, Czech Republic; 10Mayo Clinic, Rochester, MN; 11Oregon Health & Science University, Portland, OR.
Background: EVE significantly improved median progression-free survival vs PBO in patients with pNET by 6.4 months in RADIANT-3 (11.0 vs 4.6 months; HR, 0.35; 95% CI, 0.27–0.45; P < 0.001). Here we present final OS results and safety findings.
Methods: Patients with progressive advanced, low- or intermediate-grade pNET were randomized to EVE 10 mg/d (n = 207) or PBO (n = 203); both with best supportive care. Upon disease progression during double-blind phase, crossover from PBO to open-label EVE was allowed. At the time of unblinding (cutoff, June 3, 2010), all ongoing patients transitioned into the extension phase to receive open-label EVE. After 256 events, OS analysis was performed using a stratified log-rank test in the intent-to-treat patient population (N = 410; all randomized patients).
Results: Of 410 patients, 225 switched to open-label EVE; including 85% of patients initially randomized to PBO (172 of 203). Median open-label EVE exposure was 67.1 weeks (range, 1–189) in patients initially randomized to EVE and 44.0 weeks (range, 0–261) in patients randomized to PBO. Median OS (95% CI) was 44.0 (35.6–51.8) months for EVE arm and 37.7 (29.1–45.8) months for PBO arm (HR, 0.94; 95% CI, 0.73–1.20; P = 0.30; significance boundary, 0.0249). Adverse events reported during the open-label phase (n = 221) were consistent with those observed during blinded treatment; the most common included stomatitis (47%), diarrhea (44%), and rash (40%).
Clinical and Immunohistochemical Features of High Grade Neuroendocrine Neoplasia of the Gastrointestinal Tract
Allison Zemek,1 Michael A. DiMaio,1 Shirley S. Kwok,1 Pamela L. Kunz,2 Teri A. Longacre.11Department of Pathology, Stanford University Medical Center, Stanford, CA; 2Department of Medicine, Stanford University Medical Center, Stanford, CA.
Background: Neuroendocrine neoplasms of the gastrointestinal tract and pancreas are classified in the WHO 2010 system into three grades, using mitotic figure counts and Ki-67 indices. There is increasing evidence that neuroendocrine carcinomas, WHO grade 3, have a broad range of clinical behavior. Morphology and immunohistochemistry may aid in predicting outcome and distinguishing between poorly-differentiated neuroendocrine tumors and poorly-differentiated neuroendocrine carcinoma.
Methods: A retrospective search of the surgical pathology database of a large academic medical center identified 19 cases diagnosed as neuroendocrine carcinoma of gastrointestinal tract or pancreas over the past 12 years. H&E sections were examined and classified as well-differentiated neuroendocrine tumor (WDNET), poorly-differentiated neuroendocrine tumor (PDNET), or poorly-differentiated neuroendocrine carcinoma (PDNEC) based on morphologic features (cytology, trabecular/nested versus sheet-like growth, mitotic activity). Immunohistochemistry for Ki-67, p53, and p16 was performed on each tumor. Survival data were also analyzed.
Results: Of 19 tumors initially diagnosed as neuroendocrine carcinoma, 5 were reclassified as WDNET, 7 as PDNET, and 7 PDNEC based on morphologic features. WDNETs had low-grade cytology and mitotic figures less than 20 per 10 high power fields, PDNECs demonstrated high grade cytology, sheet-like growth, and higher mitotic activity. PDNETs had intermediate features. Ki-67, p53, and p16 expression data are shown in Table 1. P53 expression in less than 30% of the tumor was considered negative.
Conclusion: Tumors with features of well-differentiated neuroendocrine tumors do not express p53 and rarely express p16. Poorly-differentiated neuroendocrine tumors exhibit Ki-67 indices between 15-40%, with intermediate expression of p53 and p16. Poorly-differentiated neuroendocrine carcinoma with Ki-67 expression greater than 40% had the highest levels of p53 and p16 expression and the worst survival from the time of diagnosis. These data suggest that patients with neuroendocrine neoplasms of the gastrointestinal tract currently classified as WHO grade 3 have variable survival, and expression of p53 and p16 correlate with increasing grade and worse survival.
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